U.S. patent application number 13/404462 was filed with the patent office on 2012-06-21 for bicyclic and tricyclic derivatives as thrombin receptor antagonists.
Invention is credited to Samuel Chackalamannil, Mariappan V. Chelliah, Yuguang Wang, Yan Xia.
Application Number | 20120157403 13/404462 |
Document ID | / |
Family ID | 39269039 |
Filed Date | 2012-06-21 |
United States Patent
Application |
20120157403 |
Kind Code |
A1 |
Chackalamannil; Samuel ; et
al. |
June 21, 2012 |
BICYCLIC AND TRICYCLIC DERIVATIVES AS THROMBIN RECEPTOR
ANTAGONISTS
Abstract
Heterocyclic-substituted tricyclics of the formula ##STR00001##
or a pharmaceutically acceptable salt or solvate of said compound,
isomer or racemic mixture wherein represents an optional double
bond, the dotted line is optionally a bond or no bond, resulting in
a double bond or a single bond, as permitted by the valency
requirement and wherein E, A, G M, Het, B, X, R.sup.3, R.sup.10,
R.sup.11, R.sup.32 and R.sup.33 are herein defined and the
remaining substituents are as defined in the specification, are
disclosed, as well as pharmaceutical compositions containing them
and a method of treating diseases associated with thrombosis,
atherosclerosis, restenosis, hypertension, angina pectoris,
arrhythmia, heart failure, and cancer by administering said
compounds. Combination therapy with other cardiovascular agents is
also claimed.
Inventors: |
Chackalamannil; Samuel;
(Califon, NJ) ; Chelliah; Mariappan V.; (Edison,
NJ) ; Wang; Yuguang; (Monroe, NJ) ; Xia;
Yan; (Edison, NJ) |
Family ID: |
39269039 |
Appl. No.: |
13/404462 |
Filed: |
February 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11865793 |
Oct 2, 2007 |
8153664 |
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13404462 |
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60849354 |
Oct 4, 2006 |
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Current U.S.
Class: |
514/47 ; 514/161;
514/248; 514/249; 514/250; 514/266.21; 514/267; 514/290; 514/301;
514/307; 514/309; 514/312; 514/314; 514/337; 514/338; 514/339;
514/56; 544/234; 544/235; 544/237; 544/249; 544/284; 544/344;
544/353; 546/101; 546/110; 546/141; 546/148; 546/157; 546/176;
546/268.4; 546/268.7; 546/269.1; 546/270.1; 546/271.1; 546/271.7;
546/272.1; 546/273.1; 546/275.7; 546/276.7; 546/277.7; 546/281.1;
546/284.1 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
15/10 20180101; A61P 19/00 20180101; A61P 27/06 20180101; A61P 9/06
20180101; A61P 17/06 20180101; A61P 7/12 20180101; A61P 25/06
20180101; A61P 9/04 20180101; A61P 15/00 20180101; A61P 3/10
20180101; A61P 19/02 20180101; A61P 11/00 20180101; C07D 401/06
20130101; A61P 7/00 20180101; A61P 9/12 20180101; A61P 11/06
20180101; A61P 17/00 20180101; C07D 417/06 20130101; A61P 1/00
20180101; A61P 17/02 20180101; A61P 27/02 20180101; A61P 7/02
20180101; A61P 9/00 20180101; A61P 37/06 20180101; A61P 3/14
20180101; A61P 19/10 20180101; A61P 29/00 20180101; A61P 35/00
20180101; A61P 1/02 20180101; A61P 43/00 20180101; A61P 9/10
20180101; A61P 25/00 20180101; A61P 25/28 20180101; A61P 13/10
20180101; A61P 11/08 20180101; A61P 13/12 20180101 |
Class at
Publication: |
514/47 ;
546/284.1; 546/276.7; 544/234; 546/271.1; 546/271.7; 546/273.1;
546/281.1; 546/275.7; 546/270.1; 546/272.1; 546/269.1; 546/268.7;
546/268.4; 546/101; 544/249; 544/344; 546/110; 546/277.7; 546/148;
546/176; 544/235; 544/237; 544/284; 544/353; 546/157; 546/141;
514/339; 514/337; 514/248; 514/338; 514/290; 514/267; 514/250;
514/307; 514/314; 514/312; 514/309; 514/249; 514/266.21; 514/161;
514/301; 514/56 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076; C07D 401/08 20060101 C07D401/08; C07D 417/08 20060101
C07D417/08; C07D 413/08 20060101 C07D413/08; C07D 409/08 20060101
C07D409/08; A61K 31/4439 20060101 A61K031/4439; A61K 31/443
20060101 A61K031/443; A61K 31/5025 20060101 A61K031/5025; A61K
31/4436 20060101 A61K031/4436; A61K 31/473 20060101 A61K031/473;
A61K 31/517 20060101 A61K031/517; A61K 31/498 20060101 A61K031/498;
A61K 31/4725 20060101 A61K031/4725; A61K 31/4709 20060101
A61K031/4709; A61K 31/616 20060101 A61K031/616; A61K 31/4365
20060101 A61K031/4365; A61K 31/727 20060101 A61K031/727; A61P 7/02
20060101 A61P007/02; A61P 9/10 20060101 A61P009/10; A61P 9/12
20060101 A61P009/12; A61P 9/00 20060101 A61P009/00; A61P 9/06
20060101 A61P009/06; A61P 9/04 20060101 A61P009/04; A61P 13/12
20060101 A61P013/12; A61P 15/00 20060101 A61P015/00; A61P 29/00
20060101 A61P029/00; A61P 1/16 20060101 A61P001/16; A61P 11/00
20060101 A61P011/00; A61P 1/00 20060101 A61P001/00; A61P 37/06
20060101 A61P037/06; A61P 25/00 20060101 A61P025/00; A61P 19/10
20060101 A61P019/10; A61P 13/10 20060101 A61P013/10; A61P 3/10
20060101 A61P003/10; A61P 35/00 20060101 A61P035/00; A61P 25/28
20060101 A61P025/28; A61P 27/06 20060101 A61P027/06; A61P 11/06
20060101 A61P011/06; A61P 27/02 20060101 A61P027/02; A61P 17/06
20060101 A61P017/06; A61P 1/02 20060101 A61P001/02; C07D 405/08
20060101 C07D405/08 |
Claims
1. A compound represented by structural formula I: ##STR00173## or
a pharmaceutically acceptable salt, solvate, ester or prodrug of
said compound, wherein represents a double bond or a single bond,
as permitted by the valency requirement; with the proviso that
R.sup.3 is absent when the carbon to which R.sup.3 would be
attached is part of a double bond; B is --(CH.sub.2).sub.n3--,
--(CH.sub.2)--O--, --(CH.sub.2)S--, --(CH.sub.2)--NR.sup.6--,
--C(O)NR.sup.6--, --NR.sup.6C(O)--, ##STR00174##
--(CH.sub.2).sub.n4CR.sup.12.dbd.CR.sup.12a(CH.sub.2).sub.n5-- or
--(CH.sub.2).sub.n4C.ident.C(CH.sub.2).sub.n5--, wherein n.sub.3 is
0-5, n.sub.4 and n.sub.5 are independently 0-2, and R.sup.12 and
R.sup.12a are independently selected from the group consisting of
hydrogen, alkyl and halogen; A, E, G, M and J are independently
selected from the group consisting of --N(R.sup.54)--,
--(CR.sup.1R.sup.2)--, --O--, ##STR00175## --S--, --S(O)--,
--S(O).sub.2-- and ##STR00176## X is ##STR00177## --CH-- or --N--,
with the proviso that selection of A, G, M and X do not result in
adjacent oxygen or sulfur atoms; each n is 0, 1 or 2 with the
proviso that all n variables cannot be 0; Het is a mono-, bi- or
tricyclic heteroaromatic group of 5 to 14 atoms comprised of 1 to
13 carbon atoms and 1 to 4 heteroatoms independently selected from
the group consisting of N, O and S, with the proviso that there are
no adjacent oxygen or sulfur atoms present in the heteroaromatic
group, wherein a ring nitrogen can form an N-oxide or a quaternary
group with an alkyl group, wherein Het is attached to B by a carbon
atom ring member of Het, and wherein the Het group is substituted
by 1 to 4 moieties, W, wherein each W is independently selected
from the group consisting of hydrogen; alkyl; fluoroalkyl;
difluoroalkyl; trifluoroalkyl; cycloalkyl; heterocycloalkyl;
heterocycloalkyl substituted by alkyl or alkenyl; alkenyl;
R.sup.21-aryl; R.sup.21-heteroaryl; R.sup.21-arylalkyl;
R.sup.21-aryl-alkenyl; heteroaryl; heteroarylalkyl;
heteroarylalkenyl; hydroxyalkyl; dihydroxyalkyl; aminoalkyl;
alkylaminoalkyl; di-(alkyl)-aminoalkyl; thioalkyl; alkoxy;
alkenyloxy; halogen; --NR.sup.4R.sup.5; --CN; --OH;
--C(O)OR.sup.17; --COR.sup.16; --OS(O.sub.2)CF.sub.3;
--CH.sub.2OCH.sub.2CF.sub.3; alkylthio; --C(O)NR.sup.4R.sup.5;
--OCHR.sup.6-phenyl; phenoxyalkyl; --NHCOR.sup.16;
--NHSO.sub.2R.sup.16; biphenyl; --OC(R.sup.6).sub.2COOR.sup.7;
--OC(R.sup.6).sub.2C(O)NR.sup.4R.sup.5; alkoxy substituted by
alkyl, amino or --NHC(O)OR.sup.17; aryl; or alkyl optionally
substituted with --NR.sup.1R.sup.2, --NR.sup.1COR.sup.2,
--NR.sup.1CONR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1, --CONR.sup.1R.sup.2, hydroxyalkyl, alkyl
or --S(O).sub.2-alkyl; --C(O)NR.sup.4R.sup.5 and heteroaryl;
wherein adjacent carbons on the Het ring can optionally form a ring
with a methylenedioxy group; R.sup.1 and R.sup.2 are independently
selected from the group consisting of hydrogen, alkyl, fluoroalkyl,
difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,
arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl,
hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl;
or R.sup.1 and R.sup.2 when attached to nitrogen, taken together,
form a mono or bicyclic heterocyclic ring of 4 to 10 atoms, with
1-3 heteroatoms selected from --O--, --N--, --S--, --S(O)--,
--S(O).sub.2-- and ##STR00178## with the proviso that S and O ring
atoms are not adjacent to each other, where said heterocyclic ring
is unsubstituted or substituted with one or more groups selected
from alkyl, halogen, hydroxy, alkoxy, aryloxy and arylalkoxy;
R.sup.3 is aralkoxy, aryloxy, heteroaryl, heteroaralkoxy, --CN,
--NO.sub.2, --O-aryl, --O-heteroaryl, N.sub.3,
--C(O)NR.sup.18R.sup.19, --C(.dbd.NR.sup.1)NR.sup.1, R.sup.2,
--N(R.sup.1)C.dbd.(NR.sup.1)NR.sup.1R.sup.2;
--N.dbd.C(R.sup.1)NR.sup.1R.sup.2, --NR.sup.18C(O)R.sup.19,
--NR.sup.18C(O)NR.sup.18R.sup.19, --NR.sup.18C(O)OR.sup.19,
--NR.sup.18S(O).sub.2R.sup.19,
--NR.sup.18S(O).sub.2NR.sup.18R.sup.19, --NHNR.sup.18R.sup.19,
--NR.sup.18NR.sup.18R.sup.19 or -alkyl-NR.sup.18R.sup.19; R.sup.6
is hydrogen, alkyl or phenyl; R.sup.7 is hydrogen or alkyl; each
R.sup.13 is independently selected from hydrogen, alkyl,
cycloalkyl, haloalkyl, halogen,
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29, where n.sub.6 is 0-4;
each R.sup.14 is independently selected from the group consisting
of hydrogen, alkyl, --OH, alkoxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen,
haloalkyl, --(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4;
where R.sup.4 and R.sup.5 are independently selected from the group
consisting of hydrogen, alkyl, phenyl, benzyl and cycloalkyl, or
R.sup.4 and R.sup.5 together can form a ring with the nitrogen to
which they are attached, wherein said ring formed by R.sup.4 and
R.sup.5 is optionally substituted with .dbd.O, OH, OR.sup.1 or
--C(O)OH; or R.sup.13 and R.sup.14 taken together form a
spirocyclic or a heterospirocyclic ring of 3-6 ring atoms, wherein
said heterospirocyclic ring contains 2 to 5 carbon ring atoms and 1
or 2 hetero ring atoms selected from the group consisting of O, S
and N; R.sup.16 is independently selected from the group consisting
of hydrogen, alkyl, phenyl and benzyl; R.sup.16a is independently
selected from the group consisting of hydrogen, alkyl, phenyl and
benzyl; R.sup.16b is hydrogen, alkoxy, alkyl, alkoxyalkyl-,
R.sup.22--O--C(O)-alkyl-, cycloalkyl, R.sup.21-aryl,
R.sup.21-arylalkyl, haloalkyl, alkenyl, halo substituted alkenyl,
alkynyl, halo substituted alkynyl, R.sup.21-heteroaryl,
(R.sup.21-heteroaryl)-alkyl-, (R.sup.21-heterocycloalkyl)-alkyl-,
R.sup.28R.sup.29N-alkyl-, R.sup.28R.sup.29N--C(O)-alkyl-,
R.sup.28R.sup.29N--C(O)O-alkyl-, R.sup.28OC(O)N(R.sup.29)-alkyl-,
R.sup.28R.sup.29N-alkyl-,
R.sup.28R.sup.29N--C(O)--N(R.sup.29)-alkyl-,
R.sup.28R.sup.29N--S(O).sub.2N(R.sup.29)-alkyl-,
R.sup.28--C(O)N(R.sup.29)-alkyl-,
R.sup.28R.sup.29N--S(O).sub.2-alkyl-, HOS(O).sub.2-alkyl-,
(OH).sub.2P(O).sub.2-alkyl-, R.sup.28--S-alkyl-,
R.sup.28--S(O).sub.2-alkyl- or hydroxyalkyl; R.sup.17 is
independently selected from the group consisting of hydrogen,
alkyl, phenyl and benzyl; R.sup.18 and R.sup.19 are hydrogen,
alkyl, aryl, R.sup.21-aryl, heteroaryl, cycloalkyl, heterocyclyl,
alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl,
heteroaryloxyalkyl, heteroarylalkoxyalkyl, cycloalkyloxyalkyl,
(heterocyclyl)alkyloxyalkyl, alkoxyalkyloxyalkyl,
--S(O).sub.2-alkyl, --C(NH)NR.sup.1R.sup.2 or alkyl substituted
with one or two moieties selected from cycloalkyl, halogen,
hydroxy, --NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1 and --C(O)NR.sup.1R.sup.2; or R.sup.18 and
R.sup.19 together with the nitrogen to which they are attached,
form a mono or bicyclic heterocyclic ring of 4 to 10 atoms, having
1-3 hetero ring atoms selected from --O--, --N--, --S--, --S(O)--,
--S(O).sub.2- and ##STR00179## with the proviso that S and O atoms
are not adjacent to each other, the ring being unsubstituted or
substituted with one or more groups selected from alkyl, halogen,
hydroxy, alkoxy, aryloxy, arylalkoxy, --NR.sup.1R.sup.2,
--NR.sup.1COR.sup.2, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.2, --NR.sup.1S(O).sub.2R.sup.2,
--NR.sup.1S(O.sub.2)NR.sup.1R.sup.2, --C(O)OR.sup.1,
--CONR.sup.1R.sup.2 and alkyl substituted with --NR.sup.1R.sup.2,
--NR.sup.1COR.sup.2, --NR.sup.1CONR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.2, --NR.sup.1S(O).sub.2R.sup.2,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(O)OR.sup.1 or
--CONR.sup.1R.sup.2; R.sup.21 is 1 to 3 moieties and each R.sup.21
is independently selected from the group consisting of hydrogen,
--CN, --CF.sub.3, --OCF.sub.3, halogen, --NO.sub.2, alkyl, --OH,
alkoxy, alkylamino-, di-(alkyl)amino-, --NR.sup.25R.sup.26alkyl-,
hydroxyalkyl-, --C(O)OR.sup.17, --COR.sup.17, --NHCOR.sup.16,
--NHS(O).sub.2R.sup.16, --C(NH)--NH.sub.2,
--NHS(O).sub.2CH.sub.2CF.sub.3, --C(O)NR.sup.25R.sup.26,
--NR.sup.25--C(O)--NR.sup.25R.sup.26, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --SR.sup.13; --SO.sub.2NR.sup.4R.sup.5 and
--CONR.sup.4R.sup.5; or two adjacent R.sup.21 moieties can form a
methylenedioxy group; R.sup.22 is hydrogen, alkyl, phenyl, benzyl,
--COR.sup.16, --CONR.sup.18R.sup.19, --COR.sup.23, --S(O)R.sup.31,
--S(O).sub.2R.sup.31, --S(O.sub.2)NR.sup.24R.sup.25 or
--C(O)OR.sup.27; R.sup.23 is ##STR00180## wherein R.sup.35 and
R.sup.36 are independently selected from the group consisting of
hydrogen, alkyl, and R.sup.37-substituted alkyl, wherein R.sup.37
is selected from the group consisting of HO--, HS--, CH.sub.2S--,
--NH.sub.2, phenyl, p-hydroxyphenyl and indolyl; or R.sup.23 is
alkyl; haloalkyl; alkenyl; haloalkenyl; alkynyl; cycloalkyl;
cycloalkylalkyl; cycloalkyl substituted by 1 to 3 substituents
selected from the group consisting of alkoxyalkyl, alkyl, halogen,
hydroxy, alkoxy, aryloxy, arylalkoxy, --NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.2, --NR.sup.1S(O).sub.2R.sup.2,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(O)OH, --C(O)OR.sup.1 and
--CONR.sup.1R.sup.2; aryl; aralkyl; heteroaryl; heterocycloalkyl;
alkyl substituted with --NR.sup.1R.sup.2, --NR.sup.1COR.sup.2,
--NR.sup.1CONR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O.sub.2)R.sup.2, --NR.sup.1S(O.sub.2)NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1, --CONR.sup.1R.sup.2 and --SO.sub.3H;
R.sup.24, R.sup.25 and R.sup.26 are independently selected from the
group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,
aryl, aralkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, hydroxy and
alkoxy; R.sup.27 is 1 to 3 moieties and each R.sup.27 is selected
from the group consisting of hydrogen, alkyl, and cycloalkyl,
wherein R.sup.27 is optionally substituted with --OH, --C(O)OH,
halogen and alkoxy; R.sup.28 and R.sup.29 are independently
selected from the group consisting of hydrogen, alkyl, alkoxy,
arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl,
heterocyclyl, heterocyclylalkyl, and haloalkyl; or R.sup.28 and
R.sup.29 taken together form a spirocyclic or a heterospirocyclic
ring having 3-6 ring atoms; R.sup.32 and R.sup.33 are independently
selected from the group consisting of hydrogen, R.sup.34-alkyl,
R.sup.34-alkenyl, R.sup.34-alkynyl, R.sup.40-heterocycloalkyl,
R.sup.38-aryl, R.sup.38-aralkyl, R.sup.42-cycloalkyl,
R.sup.42-cycloalkenyl, --OH, --OC(O)R.sup.43, --C(O)OR.sup.43,
--C(O)R.sup.43, --C(O)NR.sup.43R.sup.44, --NR.sup.43R.sup.44,
--NR.sup.43C(O)R.sup.44, --NR.sup.43C(O)NR.sup.44R.sup.45,
--NHS(O).sub.2R.sup.43, --OC(O)NR.sup.43R.sup.44, R.sup.37-alkoxy,
R.sup.37-alkenyloxy, R.sup.37-alkynyloxy,
R.sup.40-heterocycloalkyloxy, R.sup.42-cycloalkyloxy,
R.sup.42-cyclo-alkenyloxy, R.sup.42-cycloalkyl-NH--,
--NHSO.sub.2NHR.sup.16 and --CH(.dbd.NOR.sup.17); or R.sup.32 and
R.sup.33 can be combined to form a ring structure Q, below
##STR00181## where R.sup.9 is hydrogen, OH, alkoxy, halogen or
haloalkyl; Q is fused R-substituted aryl, R-substituted heteroaryl,
R-substituted heterocyclic ring of 4-8 atoms containing 1-3
heteroatoms selected from O, S, S(O), S(O).sub.2 and NR.sup.22 with
the proviso that S and O cannot be adjacent to one another; or Q is
##STR00182## wherein R.sup.10 and R.sup.11 are independently
selected from the group consisting of R.sup.1 and --OR.sup.1,
provided that when ring Q is aromatic and the carbon atoms bearing
R.sup.10 and R.sup.11 are connected by a double bond, R.sup.10 and
R.sup.11 are absent; R is 1 to 5 moieties and each R is
independently selected from the group consisting of hydrogen,
alkyl, halogen, hydroxy, amino, alkylamino, dialkylamino, alkoxy,
--COR.sup.16, --C(O)OR.sup.17, --C(O)NR.sup.4R.sup.5, --SOR.sup.16,
--S(O.sub.2)R.sup.16, --NR.sup.16COR.sup.16a,
--NR.sup.16C(O)OR.sup.16a, --NR.sup.16CONR.sup.4R.sup.5,
--NR.sup.16S(O.sub.2)NR.sup.4R.sup.5, fluoroalkyl, difluoroalkyl,
trifluoroalkyl, cycloalkyl, alkenyl, arylalkyl, arylalkenyl,
heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl
and thioalkyl; R.sup.34 is 1 to 3 moieties and each R.sup.34 is
independently selected from the group consisting of hydrogen,
halogen, --OH, alkoxy, R.sup.47-aryl, alkyl-C(O)--, alkenyl-C(O)--,
alkynyl-C(O)--, heterocycloalkyl, R.sup.39-cycloalkyl,
R.sup.39-cycloalkenyl, --OC(O)R.sup.43, --C(O)OR.sup.43,
--C(O)R.sup.43, --C(O)NR.sup.43R.sup.44, --NR.sup.43R.sup.44,
--NR.sup.43C(O)R.sup.44, --NR.sup.43C(O)NR.sup.44R.sup.45,
--NHSO.sub.2R.sup.43, --OC(O)NR.sup.43R.sup.44,
R.sup.34-alkenyloxy, R.sup.34-alkynyloxy,
R.sup.40-heterocycloalkyloxy, R.sup.42-- cycloalkyloxy,
R.sup.42-cycloalkenyloxy, R.sup.42-cycloalkyl-NH--,
--NHSO.sub.2NHR.sup.16 and --CH(.dbd.NOR.sup.17); R.sup.38 is 1 to
3 moieties and each R.sup.38 is independently selected from the
group consisting of hydrogen, heterocycloalkyl, halogen,
--C(O)OR.sup.48, --CN, --C(O)NR.sup.49R.sup.50,
--NR.sup.51C(O)R.sup.52, --OR.sup.48, cycloalkyl, cycloalkylalkyl,
alkylcycloalkylalkyl, haloalkylcycloalkylalkyl, hydroxyalkyl,
alkoxyalkyl, and R.sup.52-heteroaryl; or two R.sup.38 groups on
adjacent ring carbons form a fused methylenedioxy group; R.sup.39
is 1 to 3 moieties and each R.sup.39 is independently selected from
the group consisting of hydrogen, halogen and alkoxy; R.sup.40 is 1
to 3 moieties and each R.sup.40 is independently selected from the
group consisting of hydrogen, R.sup.41-alkyl, R.sup.41-alkenyl and
R.sup.41-alkynyl; R.sup.41 is hydrogen, --OH or alkoxy; R.sup.42 is
1 to 3 moieties and each R.sup.42 is independently selected from
the group consisting of hydrogen, alkyl, --OH, alkoxy and halogen;
R.sup.43, R.sup.44 and R.sup.45 are independently selected from the
group consisting of hydrogen, alkyl, alkoxyalkyl,
R.sup.38-arylalkyl, R.sup.46-cycloalkyl, R.sup.53-cycloalkylalkyl,
R.sup.38-aryl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl
and heteroarylalkyl; R.sup.46 is hydrogen, alkyl, hydroxyalkyl or
alkoxy; R.sup.47 is 1 to 3 moieties and each R.sup.47 is
independently selected from the group consisting of hydrogen,
alkyl, --OH, halogen, --CN, alkoxy, trihaloalkoxy, alkylamino,
di(alkyl)amino, --OCF.sub.3, hydroxyalkyl, --CHO, --C(O)alkylamino,
--C(O)di(alkyl)amino, --NH.sub.2, --NHC(O)alkyl and
--N(alkyl)C(O)alkyl; R.sup.48 is hydrogen, alkyl, haloalkyl,
dihaloalkyl or trifluoroalkyl; R.sup.49 and R.sup.50 are
independently selected from the group consisting of hydrogen,
alkyl, aralkyl, phenyl and cycloalkyl, or R
.sup.49 and R.sup.50 together are --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5-- or
--(CH.sub.2).sub.2--NR.sup.39--(CH.sub.2).sub.2-- and form a ring
with the nitrogen to which they are attached; R.sup.51 and R.sup.52
are independently selected from the group consisting of hydrogen,
alkyl, aralkyl, phenyl and cycloalkyl, or R.sup.51 and R.sup.52 in
the group --NR.sup.39C(O)R.sup.40, together with the nitrogen atoms
to which they are attached, form a cyclic lactam having 5-8 ring
members; R.sup.53 is hydrogen, alkoxy, --SOR.sup.16,
--SO.sub.2R.sup.17, --C(O)OR.sup.17, --C(O)NR.sup.18R.sup.19,
alkyl, halogen, fluoroalkyl, difluoroalkyl, trifluoroalkyl,
cycloalkyl, alkenyl, aralkyl, arylalkenyl, heteroarylalkyl,
heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl, thioalkyl,
alkoxyalkyl or alkylaminoalkyl; and R.sup.54 is selected from the
group consisting of hydrogen; alkyl; fluoroalkyl; difluoroalkyl;
trifluoroalkyl; cycloalkyl; cycloalkyl substituted by 1 to 3
substituents selected from the group consisting of alkoxyalkyl,
alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy,
--NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1 and --CONR.sup.1R.sup.2; alkenyl; alkoxy;
arylalkyl; arylalkenyl; heteroarylalkyl; heteroarylalkenyl;
hydroxy; alkoxy; hydroxyalkyl; alkoxyalkyl; aminoalkyl; aryl;
heteroaryl; thioalkyl and alkyl substituted by 1 to 3 substituents
selected from the group consisting of urea, sulfonamide,
carboxamide, carboxylic acid, carboxylic ester and sulfonyl
urea.
2. A compound of claim 1 wherein ##STR00183## ##STR00184##
##STR00185##
3. A compound of claim 2 wherein ##STR00186##
4. A compound of claim 1 wherein E is --O--; A is --O--,
##STR00187## or --(CR.sup.1R.sup.2)--; G is ##STR00188## or
--(CR.sup.1R.sup.2)--; M is --(CR.sup.1R.sup.2)--; X is --C(H)--;
R.sup.3 is H; R.sup.9 is H; R.sup.10 is H or alkyl; R.sup.11 is H
or alkyl; R.sup.32 is H or alkyl; R.sup.33 is H or alkyl; B is
CR.sup.12.dbd.cR.sup.12a-- R.sup.12 and R.sup.12a are H; Het is
aryl, aryl substituted by W, heteroaryl or heteroaryl substituted
by W; and W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
5. A compound of claim 1 wherein E is --O--; A is ##STR00189## G is
--CH.sub.2--; X is --C(H)--; R.sup.3 is H; R.sup.9 is H; R.sup.10
is H or --CH.sub.3; R.sup.11 is H or --CH.sub.3; R.sup.32 is H or
--CH.sub.3; R.sup.33 is H or --CH.sub.3; B is --CH.dbd.CH--; Het is
##STR00190## and W is ##STR00191##
6. A compound of claim 1 wherein E is --O--; A is --O--,
##STR00192## or --(CR.sup.1R.sup.2)--; G is ##STR00193## or
--(CR.sup.1R.sup.2)--; M is --(CR.sup.1R.sup.2)--; X is --C(H)--;
R.sup.3 is H; R.sup.9 is H; R.sup.10 is H or alkyl; R.sup.11 is H
or alkyl; R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below ##STR00194## where Q is ##STR00195## Het is
aryl, aryl substituted by W, heteroaryl or heteroaryl substituted
by W; and W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
7. A compound of claim 1 wherein E is --O--; A is ##STR00196## G is
--CH.sub.2--; X is --C(H)--; R.sup.3 is H; R.sup.9 is H; R.sup.10
is H or --CH.sub.3; R.sup.11 is H or --CH.sub.3; R.sup.32 and
R.sup.33 are combined to form a ring structure Q, below
##STR00197## where Q is ##STR00198## B is --CH.dbd.CH--; Het is
##STR00199## and W is ##STR00200##
8. A compound of claim 1 wherein E is --N(H)-- or --N(alkyl)-; A is
--N(H)--, --N(alkyl)-, ##STR00201## or --(CR.sup.1R.sup.2)--; G is
##STR00202## or --(CR.sup.1R.sup.2)--; M is --(CR.sup.1R.sup.2)--;
X is --C(H)--; R.sup.3 is H; R.sup.9 is H; R.sup.10 is H or alkyl;
R.sup.11 is H or alkyl; R.sup.32 and R.sup.33 are combined to form
a ring structure Q, below ##STR00203## where Q is ##STR00204## Het
is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and W is aryl or aryl substituted with the 1 to 3
moieties comprising halogen, alkyl, --CF.sub.3, --CN, --OH or
--O-alkyl.
9. A compound of claim 1 wherein E is --N(H)-- or --N(alkyl)-; A is
##STR00205## G is --CH.sub.2--; X is --C(H)--; R.sup.3 is H;
R.sup.9 is H; R.sup.10 is H or --CH.sub.3; R.sup.11 is H or
--CH.sub.3; R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below ##STR00206## where Q is ##STR00207## B is
--CH.dbd.CH--; Het is ##STR00208## and W is ##STR00209##
10. A compound of claim 1 wherein E is ##STR00210## A is --N(H)--
or --N(alkyl)-; G is --N.dbd.; M is --(CR.sup.1R.sup.2)--; X is
--C(H)--; R.sup.3 is H; R.sup.9 is H; R.sup.10 is H or alkyl;
R.sup.11 is H or alkyl; R.sup.32 and R.sup.33 are combined to form
a ring structure Q, below ##STR00211## where Q is ##STR00212## Het
is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and W is aryl or aryl substituted with the 1 to 3
moieties comprising halogen, alkyl, --CF.sub.3, --CN, --OH or
--O-alkyl.
11. A compound of claim 10 wherein A is --N(H)-- or
--N(CH.sub.3)--; R.sup.10 is H or --CH.sub.3; R.sup.11 is H or
--CH.sub.3; R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below ##STR00213## where Q is ##STR00214## B is
--CH.dbd.CH--; ##STR00215## Het is and W is ##STR00216##
12. A compound of claim 1 wherein E is --O--; A is --O--,
##STR00217## or --(CR.sup.1R.sup.2)--; G is ##STR00218## or
--(CR.sup.1R.sup.2)--; M is --(CR.sup.1R.sup.2)--; X is --C(H)--;
R.sup.3 is H; R.sup.9 is H; R.sup.10 is H or alkyl; R.sup.11 is H
or alkyl; R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below ##STR00219## where Q is ##STR00220## Het is
aryl, aryl substituted by W, heteroaryl or heteroaryl substituted
by W; and W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
13. A compound of claim 1 wherein E is --O--; A is ##STR00221## G
is --CH(CH.sub.3)--; X is --C(H)--; R.sup.3 is H; R.sup.9 is H;
R.sup.10 is H or --CH.sub.3; R.sup.11 is H or --CH.sub.3; R.sup.32
and R.sup.33 are combined to form a ring structure Q, below
##STR00222## where Q is ##STR00223## B is --CH.dbd.CH--; Het is
##STR00224## and W is ##STR00225##
14. A compound selected from the group consisting of: ##STR00226##
##STR00227## ##STR00228##
15. A compound of claim 1 wherein ##STR00229##
16. A compound of claim 15 wherein ##STR00230## ##STR00231##
##STR00232## ##STR00233##
17. A compound of claim 16 wherein R.sup.3 is absent or R.sup.3 is
H; R.sup.9 is H; R.sup.10 is H or alkyl; R.sup.11 is H or alkyl;
R.sup.32 is H or alkyl; R.sup.33 is H or alkyl; or R.sup.32 and
R.sup.33 are combined to form a ring structure Q, below
##STR00234## where Q is ##STR00235## B is --CH.dbd.CH-- Het is
aryl, aryl substituted by W, heteroaryl or heteroaryl substituted
by W; and W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
18. A compound of claim 17 wherein R.sup.3 is H; R.sup.9 is H;
R.sup.10 is H or --CH.sub.3; R.sup.11 is H or --CH.sub.3; R.sup.32
is H or --CH.sub.3; R.sup.33 is H or --CH.sub.3; Het is
##STR00236## and W is ##STR00237##
19. A compound of claim 17 wherein R.sup.3 is absent or R.sup.3 is
H; R.sup.9 is H; R.sup.10 is H; R.sup.11 is H; R.sup.32 and
R.sup.33 are combined to form a ring structure Q, below
##STR00238## where Q is ##STR00239## R.sup.13 is
(--CH.sub.2).sub.n6NHC(O)OR.sup.16b; R.sup.16b is alkyl; B is
--CH.dbd.CH-- Het is aryl, aryl substituted by W, heteroaryl or
heteroaryl substituted by W; and W is aryl or aryl substituted with
the 1 to 3 moieties comprising halogen, alkyl, --CF.sub.3, --CN,
--OH or --O-alkyl.
20. A compound of claim 19 wherein R.sup.13 is
--NHC(O)OCH.sub.2CH.sub.3; Het is ##STR00240## and W is
##STR00241##
21. A compound selected from the group consisting of: ##STR00242##
##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247##
##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252##
##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257##
##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262##
##STR00263## ##STR00264## ##STR00265##
22. A compound selected from the group consisting of: ##STR00266##
##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271##
##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276##
##STR00277## ##STR00278## ##STR00279## ##STR00280##
##STR00281##
23. A pharmaceutical composition comprising an effective amount of
at least one compound of claim 1 and a pharmaceutically acceptable
carrier.
24. A method of inhibiting thrombin receptors comprising
administering to a mammal in need of such treatment an effective
amount of at least one compound of claim 1.
25. A method of treating thrombosis, atherosclerosis, restenosis,
hypertension, angina pectoris, angiogenesis related disorders,
arrhythmia, a cardiovascular or circulatory disease or condition,
heart failure, acute coronary syndrome, myocardial infarction,
glomerulonephritis, thrombotic stroke, thromboembolytic stroke,
peripheral vascular diseases, deep vein thrombosis, venous
thromboembolism, a cardiovascular disease associated with hormone
replacement therapy, disseminated intravascular coagulation
syndrome, cerebral infarction, migraine, erectile dysfunction,
rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder
of the liver, kidney, lung or intestinal tract, systemic lupus
erythematosus, multiple sclerosis, osteoporosis, renal disease,
acute renal failure, chronic renal failure, renal vascular
homeostasis, renal ischemia, bladder inflammation, diabetes,
diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis,
cancer, melanoma, renal cell carcinoma, neuropathy, malignant
tumors, neurodegenerative and/or neurotoxic diseases, conditions or
injuries, Alzheimer's disease, an inflammatory disease or
condition, asthma, glaucoma, macular degeneration, psoriasis,
endothelial dysfunction disorders of the liver, kidney or lung,
inflammatory disorders of the lungs and gastrointestinal tract,
respiratory tract disease or condition, radiation fibrosis,
endothelial dysfunction, periodontal diseases or wounds, or a
spinal cord injury, or a symptom or result thereof, comprising
administering to a mammal in need of such treatment an effective
amount of at least one compound of claim 1.
26-29. (canceled)
30. The method of claim 25 further comprising administering at
least two therapeutically effective agents.
31. A method of treating thrombosis, atherosclerosis, restenosis,
hypertension, angina pectoris, angiogenesis related disorders,
arrhythmia, a cardiovascular or circulatory disease or condition,
heart failure, acute coronary syndrome, myocardial infarction,
glomerulonephritis, thrombotic stroke, thromboembolytic stroke,
peripheral vascular diseases, deep vein thrombosis, venous
thromboembolism, a cardiovascular disease associated with hormone
replacement therapy, disseminated intravascular coagulation
syndrome, cerebral infarction, migraine, erectile dysfunction,
rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder
of the liver, kidney, lung or intestinal tract, systemic lupus
erythematosus, multiple sclerosis, osteoporosis, renal disease,
acute renal failure, chronic renal failure, renal vascular
homeostasis, renal ischemia, bladder inflammation, diabetes,
diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis,
cancer, melanoma, renal cell carcinoma, neuropathy, malignant
tumors, neurodegenerative and/or neurotoxic diseases, conditions or
injuries, Alzheimer's disease, an inflammatory disease or
condition, asthma, glaucoma, macular degeneration, psoriasis,
endothelial dysfunction disorders of the liver, kidney or lung,
inflammatory disorders of the lungs and gastrointestinal tract,
respiratory tract disease or condition, radiation fibrosis,
endothelial dysfunction, periodontal diseases or wounds, or a
spinal cord injury, or a symptom or result, comprising
administering to a mammal in need of such treatment an effective
amount of at least one compound of claim 1 in combination with at
least one additional cardiovascular agent.
32. The method of claim 31 wherein the additional cardiovascular
agent or agents is selected from the group consisting of
thromboxane A2 biosynthesis inhibitors, GP IIb/IIIa antagonists,
thromboxane antagonists, adenosine diphosphate inhibitors,
cyclooxygenase inhibitors, angiotensin antagonists, endothelin
antagonists, angiotensin converting enzyme inhibitors, neutral
endopeptidase inhibitors, anticoagulants, diuretics, and platelet
aggregation inhibitors.
33. The method of claim 32 wherein the additional cardiovascular
agent or agents are selected from the group consisting of aspirin,
cangrelor, clopidogrel bisulfate, prasugrel and fragmin.
34-44. (canceled)
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 60/849,354 filed Oct. 4, 2006, herein
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to nor-seco himbacine
derivatives, which can be useful as thrombin receptor antagonists
in the treatment of diseases associated with thrombosis,
atherosclerosis, restenosis, hypertension, angina pectoris,
arrhythmia, heart failure, cerebral ischemia, stroke,
neurodegenerative diseases and cancer. Thrombin receptor
antagonists are also known as protease activated receptor-1 (PAR-1)
antagonists. The compounds of the invention also can be useful as
cannabinoid (CB.sub.2) receptor inhibitors for the treatment of
rheumatoid arthritis, systemic lupus erythematosus, multiple
sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke,
cerebral ischemia, nephritis, inflammatory disorders of the lungs
and gastrointestinal tract, and respiratory tract disorders such as
reversible airway obstruction, chronic asthma and bronchitis. The
invention also relates to pharmaceutical compositions comprising
said compounds.
[0003] Thrombin is known to have a variety of activities in
different cell types. Thrombin receptors are known to be present in
such cell types as human platelets, vascular smooth muscle cells,
endothelial cells and fibroblasts. It is therefore expected that
thrombin receptor antagonists will be useful in the treatment of
thrombotic, inflammatory, atherosclerotic and fibroproliferative
disorders, as well as other disorders in which thrombin and its
receptor play a pathological role.
[0004] Thrombin receptor antagonist peptides have been identified
based on structure-activity studies involving substitutions of
amino acids on thrombin receptors. In Bernatowicz et al., J. Med.
Chem., 39 (1996), p. 4879-4887, tetra- and pentapeptides are
disclosed as being potent thrombin receptor antagonists, for
example
N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH.sub.2 and
N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH.sub.2.
Peptide thrombin receptor antagonists are also disclosed in WO
94/03479, published Feb. 17, 1994.
[0005] Cannabinoid receptors belong to the superfamily of G-protein
coupled receptors. They are classified into the predominantly
neuronal CB.sub.1 receptors and the predominantly peripheral
CB.sub.2 receptors. These receptors exert their biological actions
by modulating adenylate cyclase and Ca.sup.+2 and K.sup.+ currents.
While the effects of CB.sub.1 receptors are principally associated
with the central nervous system, CB.sub.2 receptors are believed to
have peripheral effects related to bronchial constriction,
immunomodulation and inflammation. As such, a selective CB.sub.2
receptor binding agent is expected to have therapeutic utility in
the control of diseases associated with rheumatoid arthritis,
systemic lupus erythematosus, multiple sclerosis, diabetes,
osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia,
nephritis, inflammatory disorders of the lungs and gastrointestinal
tract, and respiratory tract disorders such as reversible airway
obstruction, chronic asthma and bronchitis (R. G. Pertwee, Curr.
Med. Chem. 6(8), (1999), 635; M. Bensaid, Molecular Pharmacology,
63 (4), (2003), 908.). Himbacine, a piperidine alkaloid of the
formula
##STR00002##
has been identified as a muscarinic receptor antagonist. The total
synthesis of (+)-himbacine is disclosed in Chackalamannil et al.,
J. Am. Chem. Soc., 118 (1996), p. 9812-9813.
[0006] Substituted tricyclic thrombin receptor antagonists are
disclosed in U.S. Pat. No. 6,063,847, U.S. Pat. No. 6,326,380 and
U.S. Ser. Nos. 09/880,222 (WO 01/96330) and 10/271,715.
SUMMARY OF THE INVENTION
[0007] The present invention relates to compounds represented by
the formula I:
##STR00003##
or a pharmaceutically acceptable salt, solvate, ester or prodrug of
said compound, wherein
[0008] represents a double bond or a single bond, as permitted by
the valency requirement; with the proviso that R.sup.3 is absent
when the carbon to which R.sup.3 would be attached is part of a
double bond;
[0009] B is --(CH.sub.2).sub.n3--, --(CH.sub.2)--O--,
--(CH.sub.2)S--, --(CH.sub.2)--NR.sup.6--, --C(O)NR.sup.6--,
--NR.sup.6C(O)--,
##STR00004##
--(CH.sub.2).sub.n4CR.sup.12a(CH.sub.2).sub.n5.sub.- or
--(CH.sub.2).sub.n4C.ident.C(CH.sub.2).sub.n5.sub.-, wherein
n.sub.3 is 0-5, n.sub.4 and n.sub.5 are independently 0-2, and
R.sup.12 and R.sup.12a are independently selected from the group
consisting of hydrogen, alkyl and halogen;
[0010] A, E, G, M and J are independently selected from the group
consisting of --N(R.sup.54)--, --(CR.sup.1R.sup.2)--, --O--,
##STR00005##
--S--, --S(O)--, --S(O).sub.2-- and
##STR00006##
[0012] X is
##STR00007##
--CH-- or --N--, with the proviso that selection of A, G, M and X
do not result in adjacent oxygen or sulfur atoms;
[0013] each n is 0, 1 or 2 with the proviso that all n variables
cannot be 0;
[0014] Het is a mono-, bi- or tricyclic heteroaromatic group of 5
to 14 atoms comprised of 1 to 13 carbon atoms and 1 to 4
heteroatoms independently selected from the group consisting of N,
O and S, with the proviso that there are no adjacent oxygen or
sulfur atoms present in the heteroaromatic group, wherein a ring
nitrogen can form an N-oxide or a quaternary group with an alkyl
group, wherein Het is attached to B by a carbon atom ring member of
Het, and wherein the Het group is substituted by 1 to 4 moieties,
W, wherein each W is independently selected from the group
consisting of hydrogen; alkyl; fluoroalkyl; difluoroalkyl;
trifluoroalkyl; cycloalkyl; heterocycloalkyl; heterocycloalkyl
substituted by alkyl or alkenyl; alkenyl; R.sup.21-aryl;
R.sup.21-heteroaryl; R.sup.21-arylalkyl; R.sup.21-aryl-alkenyl;
heteroaryl; heteroarylalkyl; heteroarylalkenyl; hydroxyalkyl;
dihydroxyalkyl; aminoalkyl; alkylaminoalkyl; di-(alkyl)-aminoalkyl;
thioalkyl; alkoxy; alkenyloxy; halogen; --NR.sup.4R.sup.5; --CN;
--OH; --C(O)OR.sup.17; --COR.sup.16; --OS(O.sub.2)CF.sub.3;
--CH.sub.2OCH.sub.2CF.sub.3; alkylthio; --C(O)NR.sup.4R.sup.5;
--OCHRE-phenyl; phenoxyalkyl; --NHCOR.sup.16; --NHSO.sub.2R.sup.16;
biphenyl; --OC(R.sup.6).sub.2COOR.sup.7;
--OC(R.sup.6).sub.2C(O)NR.sup.4R.sup.5; alkoxy substituted by
alkyl, amino or --NHC(O)OR.sup.17; aryl; or alkyl optionally
substituted with --NR.sup.1R.sup.2, --NR.sup.1COR.sup.2,
--NR.sup.1CONR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1, --CONR.sup.1R.sup.2, hydroxyalkyl, alkyl
or --S(O).sub.2-alkyl; --C(O)NR.sup.4R.sup.5 and heteroaryl;
wherein adjacent carbons on the Het ring can optionally form a ring
with a methylenedioxy group;
[0015] R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkyl, fluoroalkyl, difluoroalkyl,
trifluoroalkyl, cycloalkyl, alkenyl, alkoxy, arylalkyl,
arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,
hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; or
[0016] R.sup.1 and R.sup.2 when attached to nitrogen, taken
together, form a mono or bicyclic heterocyclic ring of 4 to 10
atoms, with 1-3 heteroatoms selected from --O--, --N--, --S--,
--S(O)--, --S(O).sub.2-- and
##STR00008##
with the proviso that S and O ring atoms are not adjacent to each
other, where said heterocyclic ring is unsubstituted or substituted
with one or more groups selected from alkyl, halogen, hydroxy,
alkoxy, aryloxy and arylalkoxy;
[0017] R.sup.3 is aralkoxy, aryloxy, heteroaryl, heteroaralkoxy,
--CN, --NO.sub.2, --O-aryl, --O-heteroaryl, N.sub.3,
--C(O)NR.sup.18R.sup.19, --C(.dbd.NR.sup.1)NR.sup.1R.sup.2,
--N(R.sup.1)C.dbd.(NR.sup.1)NR.sup.1, R.sup.2;
--N.dbd.C(R.sup.1)NR.sup.1R.sup.2, --NR.sup.18C(O)R.sup.19,
--NR.sup.18C(O)NR.sup.18R.sup.19, --NR.sup.18C(O)OR.sup.19,
--NR.sup.18S(O).sub.2R.sup.19,
--NR.sup.18S(O).sub.2NR.sup.18R.sup.19, --NHNR.sup.18R.sup.19,
--NR.sup.18NR.sup.18R.sup.19 or -alkyl-NR.sup.18R.sup.19;
[0018] R.sup.6 is hydrogen, alkyl or phenyl;
[0019] R.sup.7 is hydrogen or alkyl;
[0020] each R.sup.13 is independently selected from hydrogen,
alkyl, cycloalkyl, haloalkyl, halogen,
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29, where n.sub.6 is 0-4;
[0021] each R.sup.14 is independently selected from the group
consisting of hydrogen, alkyl, --OH, alkoxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen,
haloalkyl, --(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4;
where R.sup.4 and R.sup.5 are independently selected from the group
consisting of hydrogen, alkyl, phenyl, benzyl and cycloalkyl, or
R.sup.4 and R.sup.5 together can form a ring with the nitrogen to
which they are attached, wherein said ring formed by R.sup.4 and
R.sup.5 is optionally substituted with .dbd.O, OH, OR.sup.1 or
--C(O)OH; or
[0022] R.sup.13 and R.sup.14 taken together form a spirocyclic or a
heterospirocyclic ring of 3-6 ring atoms, wherein said
heterospirocyclic ring contains 2 to 5 carbon ring atoms and 1 or 2
hetero ring atoms selected from the group consisting of O, S and
N;
[0023] R.sup.16 is independently selected from the group consisting
of hydrogen, alkyl, phenyl and benzyl;
[0024] R.sup.16a is independently selected from the group
consisting of hydrogen, alkyl, phenyl and benzyl;
[0025] R.sup.16b is hydrogen, alkoxy, alkyl, alkoxyalkyl-,
R.sup.22--O--C(O)-alkyl-, cycloalkyl, R.sup.21-aryl,
R.sup.21-arylalkyl, haloalkyl, alkenyl, halo substituted alkenyl,
alkynyl, halo substituted alkynyl, R.sup.21-heteroaryl,
(R.sup.21-heteroaryl)alkyl-, (R.sup.21-heterocycloalkyl)-alkyl-,
R.sup.28R.sup.29N-alkyl-, R.sup.28R.sup.29N--C(O)-alkyl-,
R.sup.28R.sup.29N--C(O)O-alkyl-, R.sup.28OC(O)N(R.sup.29)-alkyl-,
R.sup.28S(O).sub.2N(R.sup.29)-alkyl-,
R.sup.28R.sup.29N--C(O)--N(R.sup.29)-alkyl-,
R.sup.28R.sup.29N--S(O).sub.2N(R.sup.29)-alkyl-,
R.sup.28--C(O)N(R.sup.29)-alkyl-,
R.sup.28R.sup.29N--S(O).sub.2-alkyl-, HOS(O).sub.2-alkyl-,
(OH).sub.2P(O).sub.2-alkyl-, R.sup.28--S-alkyl-,
R.sup.28--S(O).sub.2-alkyl- or hydroxyalkyl;
[0026] R.sup.17 is independently selected from the group consisting
of hydrogen, alkyl, phenyl and benzyl;
[0027] R.sup.18 and R.sup.19 are hydrogen, alkyl, aryl,
R.sup.21-aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxyalkyl,
haloalkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, heteroaryloxyalkyl,
heteroarylalkoxyalkyl, cycloalkyloxyalkyl,
(heterocyclyl)alkyloxyalkyl, alkoxyalkyloxyalkyl,
--S(O).sub.2-alkyl, --C(NH)NR.sup.1R.sup.2 or alkyl substituted
with one or two moieties selected from cycloalkyl, halogen,
hydroxy, --NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1 and --C(O)NR.sup.1R.sup.2; or
[0028] R.sup.18 and R.sup.19 together with the nitrogen to which
they are attached, form a mono or bicyclic heterocyclic ring of 4
to 10 atoms, having 1-3 hetero ring atoms selected
from --O--, --N--, --S--, --S(O)--, --S(O).sub.2- and
##STR00009##
with the proviso that S and O atoms are not adjacent to each other,
the ring being unsubstituted or substituted with one or more groups
selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy,
--NR.sup.1R.sup.2, --NR.sup.1COR.sup.2,
--NR.sup.1C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O.sub.2)NR.sup.1R.sup.2,
--C(O)OR.sup.1, --CONR.sup.1R.sup.2 and alkyl substituted with
--NR.sup.1R.sup.2, --NR.sup.1COR.sup.2,
--NR.sup.1CONR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OR.sup.1 or --CONR.sup.1R.sup.2;
[0029] R.sup.21 is 1 to 3 moieties and each R.sup.21 is
independently selected from the group consisting of hydrogen, --CN,
--CF.sub.3, --OCF.sub.3, halogen, --NO.sub.2, alkyl, --OH, alkoxy,
alkylamino-, di-(alkyl)amino-, --NR.sup.25R.sup.26alkyl-,
hydroxyalkyl-, --C(O)OR.sup.17, --COR.sup.17, --NHCOR.sup.16,
--NHS(O).sub.2R.sup.16, --C(NH)--NH.sub.2,
--NHS(O).sub.2CH.sub.2CF.sub.3, --C(O)NR.sup.25R.sup.26,
--NR.sup.25--C(O)--NR.sup.25R.sup.26, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --SR.sup.13; --SO.sub.2NR.sup.4R.sup.5 and
--CONR.sup.4, R.sup.5; or two adjacent R.sup.21 moieties can form a
methylenedioxy group;
[0030] R.sup.22 is hydrogen, alkyl, phenyl, benzyl, --COR.sup.16,
--CONR.sup.18R.sup.19, --COR.sup.23, --S(O)R.sup.31,
--S(O).sub.2R.sup.31, --S(O.sub.2)NR.sup.24R.sup.25 or
--C(O)OR.sup.27;
[0031] R.sup.23 is
##STR00010##
wherein R.sup.35 and R.sup.36 are independently selected from the
group consisting of hydrogen, alkyl, and R.sup.37-substituted
alkyl, wherein R.sup.37 is selected from the group consisting of
HO--, HS--, CH.sub.2S--, --NH.sub.2, phenyl, p-hydroxyphenyl and
indolyl; or R.sup.23 is alkyl; haloalkyl; alkenyl; haloalkenyl;
alkynyl; cycloalkyl; cycloalkylalkyl; cycloalkyl substituted by 1
to 3 substituents selected from the group consisting of
alkoxyalkyl, alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy,
--NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1 and --CONR.sup.1R.sup.2; aryl; aralkyl;
heteroaryl; heterocycloalkyl; alkyl substituted with
--NR.sup.1R.sup.2, --NR.sup.1COR.sup.2,
--NR.sup.1CONR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O.sub.2)R.sup.2, --NR.sup.1S(O.sub.2)NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1, --CONR.sup.1R.sup.2 and --SO.sub.3H;
[0032] R.sup.24, R.sup.25 and R.sup.26 are independently selected
from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl,
alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,
hydroxy and alkoxy;
[0033] R.sup.27 is 1 to 3 moieties and each R.sup.27 is selected
from the group consisting of hydrogen, alkyl, and cycloalkyl,
wherein R.sup.27 is optionally substituted with --OH, --C(O)OH,
halogen and alkoxy;
[0034] R.sup.28 and R.sup.29 are independently selected from the
group consisting of hydrogen, alkyl, alkoxy, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl,
heterocyclylalkyl, and haloalkyl; or
[0035] R.sup.28 and R.sup.29 taken together form a spirocyclic or a
heterospirocyclic ring having 3-6 ring atoms;
[0036] R.sup.32 and R.sup.33 are independently selected from the
group consisting of hydrogen, R.sup.34-alkyl, R.sup.34 alkenyl,
R.sup.34-alkynyl, R.sup.40-heterocycloalkyl, R.sup.38-aryl,
R.sup.38-aralkyl, R.sup.42-cycloalkyl, R.sup.42-cycloalkenyl, --OH,
--OC(O)R.sup.43, --C(O)OR.sup.43, --C(O)R.sup.43,
--C(O)NR.sup.43R.sup.44, --NR.sup.43R.sup.44,
--NR.sup.43C(O)R.sup.44, --NR.sup.43C(O)NR.sup.44R.sup.45,
--NHS(O).sub.2R.sup.43, --OC(O)NR.sup.43R.sup.44, R.sup.37-alkoxy,
R.sup.37-alkenyloxy, R.sup.37-alkynyloxy,
R.sup.40-heterocycloalkyloxy, R.sup.42-cycloalkyloxy,
R.sup.42-cyclo-alkenyloxy, R.sup.42-cycloalkyl-NH--,
--NHSO.sub.2NHR.sup.16 and --CH(.dbd.NOR.sup.17);
[0037] or R.sup.32 and R.sup.33 can be combined to form a ring
structure Q, below
##STR00011##
where
[0038] R.sup.9 is hydrogen, OH, alkoxy, halogen or haloalkyl;
[0039] Q is fused R-substituted aryl, R-substituted heteroaryl,
R-substituted heterocyclic ring of 4-8 atoms containing 1-3
heteroatoms selected from O, S, S(O), S(O).sub.2 and NR.sup.22 with
the proviso that S and O cannot be adjacent to one another; or
[0040] Q is
##STR00012##
[0041] wherein R.sup.10 and R.sup.11 are independently selected
from the group consisting of R.sup.1 and --OR.sup.1, provided that
when ring Q is aromatic and the carbon atoms bearing R.sup.10 and
R.sup.11 are connected by a double bond, R.sup.10 and R.sup.11 are
absent;
[0042] R is 1 to 5 moieties and each R is independently selected
from the group consisting of hydrogen, alkyl, halogen, hydroxy,
amino, alkylamino, dialkylamino, alkoxy, --COR.sup.16,
--C(O)OR.sup.17, --C(O)NR.sup.4R.sup.5, --SOR.sup.16,
--S(O.sub.2)R.sup.16, --NR.sup.16COR.sup.16a,
--NR.sup.16C(O)OR.sup.16a, --NR.sup.16CONR.sup.4R.sup.5,
--NR.sup.16S(O.sub.2)NR.sup.4R.sup.5, fluoroalkyl, difluoroalkyl,
trifluoroalkyl, cycloalkyl, alkenyl, arylalkyl, arylalkenyl,
heteroarylalkyl, heteroaryfalkenyl, hydroxyalkyl, aminoalkyl, aryl
and thioalkyl;
[0043] R.sup.34 is 1 to 3 moieties and each R.sup.34 is
independently selected from the group consisting of hydrogen,
halogen, --OH, alkoxy, R.sup.47-aryl, alkyl-C(O)--, alkenyl-C(O)--,
alkynyl-C(O)--, heterocycloalkyl, R.sup.39-cycloalkyl,
R.sup.39-cycloalkenyl, --OC(O)R.sup.43, --C(O)OR.sup.43,
--C(O)R.sup.43, --C(O)NR.sup.43R.sup.44, --NR.sup.43R.sup.44,
--NR.sup.43C(O)R.sup.44, --NR.sup.43C(O)NR.sup.44R.sup.45,
--NHSO.sub.2R.sup.43, --OC(O)NR.sup.43R.sup.44,
R.sup.34-alkenyloxy, R.sup.34-alkynyloxy,
R.sup.40-heterocycloalkyloxy, R.sup.42-cycloalkyloxy,
R.sup.42-cycloalkenyloxy, R.sup.42-cycloalkyl-NH--,
--NHSO.sub.2NHR.sup.16 and --CH(.dbd.NOR.sup.17);
[0044] R.sup.38 is 1 to 3 moieties and each R.sup.38 is
independently selected from the group consisting of hydrogen,
heterocycloalkyl, halogen, --C(O)OR.sup.48, --CN,
--C(O)NR.sup.49R.sup.50, --NR.sup.51C(O)R.sup.52, --OR.sup.48,
cycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl,
haloalkylcycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, and
R.sup.52-heteroaryl; or two R.sup.38 groups on adjacent ring
carbons form a fused methylenedioxy group;
[0045] R.sup.39 is 1 to 3 moieties and each R.sup.39 is
independently selected from the group consisting of hydrogen,
halogen and alkoxy;
[0046] R.sup.40 is 1 to 3 moieties and each R.sup.40 is
independently selected from the group consisting of hydrogen,
R.sup.41-alkyl, R.sup.41-alkenyl and R.sup.41-alkynyl;
[0047] R.sup.41 is hydrogen, --OH or alkoxy;
[0048] R.sup.42 is 1 to 3 moieties and each R.sup.42 is
independently selected from the group consisting of hydrogen,
alkyl, --OH, alkoxy and halogen;
[0049] R.sup.43, R.sup.44 and R.sup.45 are independently selected
from the group consisting of hydrogen, alkyl, alkoxyalkyl,
R.sup.38-arylalkyl, R.sup.46-cycloalkyl, R.sup.53-cycloalkylalkyl,
R.sup.38-aryl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl
and heteroarylalkyl;
[0050] R.sup.46 is hydrogen, alkyl, hydroxyalkyl or alkoxy;
[0051] R.sup.47 is 1 to 3 moieties and each R.sup.47 is
independently selected from the group consisting of hydrogen,
alkyl, --OH, halogen, --ON, alkoxy, trihaloalkoxy, alkylamino,
di(alkyl)amino, --OCF.sub.3, hydroxyalkyl, --CHO, --C(O)alkylamino,
--C(O)di(alkyl)amino, --NH.sub.2, --NHC(O)alkyl and
--N(alkyl)C(O)alkyl;
[0052] R.sup.48 is hydrogen, alkyl, haloalkyl, dihaloalkyl or
trifluoroalkyl;
[0053] R.sup.49 and R.sup.50 are independently selected from the
group consisting of hydrogen, alkyl, aralkyl, phenyl and
cycloalkyl, or R.sup.49 and R.sup.50 together are
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5-- or
--(CH.sub.2).sub.2--NR.sup.39--(CH.sub.2).sub.2-- and form a ring
with the nitrogen to which they are attached;
[0054] R.sup.51 and R.sup.52 are independently selected from the
group consisting of hydrogen, alkyl, aralkyl, phenyl and
cycloalkyl, or R.sup.51 and R.sup.52 in the group
--NR.sup.39C(O)R.sup.40, together with the nitrogen atoms to which
they are attached, form a cyclic lactam having 5-8 ring
members;
[0055] R.sup.53 is hydrogen, alkoxy, --SOR.sup.16,
--SO.sub.2R.sup.17, --C(O)OR.sup.17, --C(O)NR.sup.18R.sup.19,
alkyl, halogen, fluoroalkyl, difluoroalkyl, trifluoroalkyl,
cycloalkyl, alkenyl, aralkyl, arylalkenyl, heteroarylalkyl,
heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl, thioalkyl,
alkoxyalkyl or alkylaminoalkyl; and
[0056] R.sup.54 is selected from the group consisting of hydrogen;
alkyl; fluoroalkyl; difluoroalkyl; trifluoroalkyl; cycloalkyl;
cycloalkyl substituted by 1 to 3 substituents selected from the
group consisting of alkoxyalkyl, alkyl, halogen, hydroxy, alkoxy,
aryloxy, arylalkoxy, --NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)OR.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, --NR.sup.1S(O).sub.2NR.sup.1R.sup.2,
--C(O)OH, --C(O)OR.sup.1 and --CONR.sup.1R.sup.2; alkenyl; alkoxy;
arylalkyl; arylalkenyl; heteroarylalkyl; heteroarylalkenyl;
hydroxy; alkoxy; hydroxyalkyl; alkoxyalkyl; aminoalkyl; aryl;
heteroaryl; thioalkyl and alkyl substituted by 1 to 3 substituents
selected from the group consisting of urea, sulfonamide,
carboxamide, carboxylic acid, carboxylic ester and sulfonyl urea.
Pharmaceutical compositions comprising at least one compound of
formula I and a pharmaceutically acceptable carrier are also
provided.
[0057] The compounds of the present invention can be useful as
Thrombin receptor antagonists, also known as PAR-1 antagonists, or
as cannabinoid (CB.sub.2) receptor antagonists. Thrombin receptor
antagonist compounds of the present invention can have
anti-thrombotic, anti-platelet aggregation, anti-atherosclerotic,
anti-restenotic anti-coagulant, and/or anti-inflammatory activity.
CB.sub.2 receptor inhibitor compounds of the present invention can
be useful for the treatment of rheumatoid arthritis, systemic lupus
erythematosus, multiple sclerosis, diabetes, osteoporosis, renal
ischemia, cerebral stroke, cerebral ischemia, nephritis,
inflammatory disorders of the lungs and gastrointestinal tract, and
respiratory tract disorders such as reversible airway obstruction,
chronic asthma and bronchitis.
[0058] Compounds of the invention can be useful for the treatment
of thrombosis, atherosclerosis, restenosis, hypertension, angina
pectoris, angiogenesis related disorders, arrhythmia, a
cardiovascular or circulatory disease or condition, heart failure,
acute coronary syndrome (ACS), myocardial infarction,
glomerulonephritis, thrombotic stroke, thromboembolytic stroke,
peripheral vascular diseases, deep vein thrombosis, venous
thromboembolism, a cardiovascular disease associated with hormone
replacement therapy, disseminated intravascular coagulation
syndrome, cerebral infarction, migraine, erectile dysfunction,
rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder
of the liver, kidney, lung or intestinal tract, systemic lupus
erythematosus, multiple sclerosis, osteoporosis, renal disease,
acute renal failure, chronic renal failure, renal vascular
homeostasis, renal ischemia, bladder inflammation, diabetes,
diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis,
cancer, melanoma, renal cell carcinoma, neuropathy, malignant
tumors, neurodegenerative and/or neurotoxic diseases, conditions or
injuries, Alzheimer's disease, an inflammatory disease or
condition, asthma, glaucoma, macular degeneration, psoriasis,
endothelial dysfunction disorders of the liver, kidney or lung,
inflammatory disorders of the lungs and gastrointestinal tract,
respiratory tract disease or condition, radiation fibrosis,
endothelial dysfunction, periodontal diseases or wounds, or a
spinal cord injury, or a symptom or result thereof, as well as
other disorders in which thrombin and its receptor play a
pathological role.
[0059] In particular, compounds of the present invention can be
used to treat acute coronary syndrome, myocardial infarction of
thrombotic stroke.
[0060] Compounds of the present invention can also be used in a
method to treat or prevent a condition associated with
cardiopulmonary bypass surgery (CPB) comprising administering an
effective amount of at least one thrombin receptor antagonist to a
subject of said surgery. CPB surgery includes coronary artery
bypass surgery (CABG), cardiac valvular repair and replacement
surgery, pericardial and aortic repair surgeries. In particular,
the present invention relates to a method of treating or preventing
a condition associated with CABG surgery comprising administering
an effective amount of at least one thrombin receptor antagonist to
a subject of said surgery. The conditions associated with CABG are
selected from the group consisting of: bleeding; thrombotic
vascular events such as thrombosis, restenosis; vein graft failure;
artery graft failure; atherosclerosis, angina pectoris; myocardial
ischemia; acute coronary syndrome myocardial infarction; heart
failure; arrhythmia; hypertension; transient ischemic attack;
cerebral function impairment; thromboembolic stroke; cerebral
ischemia; cerebral infarction; thrombophlebitis; deep vein
thrombosis; and, peripheral vascular disease.
[0061] In another embodiment, compounds of the present invention
can be useful in a method for treating and/or preventing radiation-
and/or chemical-induced toxicity in non-malignant tissue in a
patient comprising administering a therapeutically effective amount
of at least one compound of formula I. In particular, the
radiation- and/or chemical-induced toxicity is one or more of
intestinal fibrosis, pneumonitis, and mucositis. In a preferred
embodiment, the radiation- and/or chemical-induced toxicity is
intestinal fibrosis. In another preferred embodiment, the
radiation- and/or chemical-induced toxicity is oral mucositis. In
yet another embodiment, the radiation- and/or chemical-induced
toxicity is intestinal mucositis, intestinal fibrosis, intestinal
radiation syndrome, or pathophysiological manifestations of
intestinal radiation exposure.
[0062] The present invention also provides methods for reducing
structural radiation injury in a patient that will be exposed, is
concurrently exposed, or was exposed to radiation and/or chemical
toxicity, comprising administering a therapeutically effective
amount of at least one compound of formula I. The present invention
also provides methods for reducing inflammation in a patient that
will be exposed, is concurrently exposed, or was exposed to
radiation and/or chemical toxicity, comprising administering a
therapeutically effective amount of at least one compound of
formula I. The present invention also provides methods for adverse
tissue remodeling in a patient that will be exposed, is
concurrently exposed, or was exposed to radiation and/or chemical
toxicity, comprising administering a therapeutically effective
amount of at least one compound of formula I. The present invention
also provides methods for reducing fibroproliferative tissue
effects in a patient that will be exposed, is concurrently exposed,
or was exposed to radiation and/or chemical toxicity, comprising
administering a therapeutically effective amount of at least one
compound of formula I.
[0063] The present invention further provides methods useful for
treating a cell proliferative disorder in a patient suffering
therefrom comprising administering a therapeutically effective
amount of at least one compound of formula I. In one embodiment,
the cell proliferative disorder is pancreatic cancer, glioma,
ovarian cancer, colorectal and/or colon cancer, breast cancer,
prostate cancer, thyroid cancer, lung cancer, melanoma, or stomach
cancer. In one embodiment, the glioma is an anaplastic astrocytoma.
In another embodiment, the glioma is a glioblastoma multiforme.
[0064] As used above, the term inflammatory disease or condition
includes irritable bowel syndrome, Crohn's disease, nephritis or a
radiation- or chemotherapy-induced proliferative or inflammatory
disorder of the gastrointestinal tract, lung, urinary bladder,
gastrointestinal tract or other organ. The term respiratory tract
disease or condition includes reversible airway obstruction,
asthma, chronic asthma, bronchitis or chronic airways disease.
"Cancer" includes renal cell carcinoma or an angiogenesis related
disorder. "Neurodegenerative disease" includes Parkinson's disease,
amyotropic lateral sclerosis, Alzheimer's disease, Huntington's
disease or Wilson's disease.
[0065] Certain embodiments of this invention also relate to a
method of using an effective amount of at least one compound of
Formula I in combination with one or more additional agents for the
treatment of thrombosis, atherosclerosis, restenosis, hypertension,
angina pectoris, angiogenesis related disorders, arrhythmia, a
cardiovascular or circulatory disease or condition, heart failure,
acute coronary syndrome (ACS), myocardial infarction,
glomerulonephritis, thrombotic stroke, thromboembolytic stroke,
peripheral vascular diseases, deep vein thrombosis, venous
thromboembolism, a cardiovascular disease associated with hormone
replacement therapy, disseminated intravascular coagulation
syndrome, cerebral infarction, migraine, erectile dysfunction,
rheumatoid arthritis, rheumatism, astrogliosis, a fibrotic disorder
of the liver, kidney, lung or intestinal tract, systemic lupus
erythematosus, multiple sclerosis, osteoporosis, renal disease,
acute renal failure, chronic renal failure, renal vascular
homeostasis, renal ischemia, bladder inflammation, diabetes,
diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis,
cancer, melanoma, renal cell carcinoma, neuropathy, malignant
tumors, neurodegenerative and/or neurotoxic diseases, conditions or
injuries, Alzheimer's disease, an inflammatory disease or
condition, asthma, glaucoma, macular degeneration, psoriasis,
endothelial dysfunction disorders of the liver, kidney or lung,
inflammatory disorders of the lungs and gastrointestinal tract,
respiratory tract disease or condition, radiation fibrosis,
endothelial dysfunction, periodontal diseases or wounds, or a
spinal cord injury, or a symptom or result thereof. It is
contemplated that a combination of this invention may be useful in
treating more than one of the diseases listed.
[0066] For treating and/or preventing radiation- and/or
chemical-induced toxicity in non-malignant tissue, the present
invention includes administering to a patient in need of such
treatment an effective amount of a combination of one or more
compounds of formula I and one or more radiation-response modifiers
selected from the group consisting of Kepivance.TM. (palifermin),
L-glutamine, teduglutide, sucralfate mouth rinses, iseganan,
lactoferrin, mesna and trefoil factor.
[0067] For treating a cell proliferative disorder the present
invention includes administering to a patient in need of such
treatment an effective amount of a combination of one or more
compounds of formula I and another antineoplastic agent. In one
embodiment, the other antineoplastic agent is temozolomide and the
cell proliferative disorder is glioma. In another embodiment, the
other antineoplastic agent is interferon and the cell proliferative
disorder is melanoma. In one embodiment, the other antineoplastic
agent is PEG-Intron (peginterferon alpha-2b) and the cell
proliferative disorder is melanoma.
[0068] Pharmaceutical compositions comprising a therapeutically
effective amount of a combination of at least one compound of
formula I and at least one additional cardiovascular agent in a
pharmaceutically acceptable carrier are also provided.
[0069] Pharmaceutical compositions comprising a therapeutically
effective amount of a combination of at least one compound of
formula I and a radiation-response modifier in a pharmaceutically
acceptable carrier are also provided.
[0070] Pharmaceutical compositions comprising a therapeutically
effective amount of a combination of at least one compound of
formula I and an antineoplastic agent in a pharmaceutically
acceptable carrier are also provided.
[0071] It is further contemplated that the combination of the
invention can be provided as a kit comprising in a single package
at least one compound of formula I in a pharmaceutical composition,
and at least one separate pharmaceutical composition comprising a
cardiovascular agent, a radiation-response modifier, or an
antineoplastic agent.
DETAILED DESCRIPTION
[0072] In one embodiment, the present invention provides compounds
represented by structural formula I, or pharmaceutically acceptable
salt thereof, wherein the various moieties are as described as
above.
[0073] For compounds of Formula I, preferred embodiments of the
compounds of formula I are as follows:
##STR00013## ##STR00014## ##STR00015##
[0074] Additional preferred embodiments of the compounds of formula
I are as follows:
##STR00016##
[0075] More preferred embodiments are those compounds of formula I
where E is --O--;
[0076] A is --O--,
##STR00017##
or --(CR.sup.1R.sup.2)--;
[0077] G is
##STR00018##
or --(CR.sup.1R.sup.2)--;
[0078] M is --(CR.sup.1R.sup.2)--;
[0079] X is --C(H)--;
[0080] R.sup.3 is H;
[0081] R.sup.9 is H;
[0082] R.sup.10 is H or alkyl;
[0083] R.sup.11 is H or alkyl;
[0084] R.sup.32 is H or alkyl;
[0085] R.sup.33 is H or alkyl;
[0086] B is --CR.sup.12.dbd.cR.sup.12a.sup.--;
[0087] R.sup.12 and R.sup.12a are H;
[0088] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0089] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0090] More preferred embodiments are those compounds of formula I
where:
[0091] E is --O--;
[0092] A is
##STR00019##
[0093] G is --CH.sub.2--;
[0094] X is --C(H)--;
[0095] R.sup.3 is H;
[0096] R.sup.9 is H;
[0097] R.sup.10 is H or --CH.sub.3--;
[0098] R.sup.11 is H or --CH.sub.3--;
[0099] R.sup.32 is H or --CH.sub.3--;
[0100] R.sup.33 is H or --CH.sub.3--;
[0101] B is --CH.dbd.CH--;
[0102] Het is
##STR00020##
and
##STR00021##
[0103] W is
[0104] In one embodiment of a compound of formula I wherein
[0105] E is --O--;
[0106] A is --O--,
##STR00022##
or --(CR.sup.1R.sup.2)--;
[0107] G is
##STR00023##
or --(CR.sup.1R.sup.2)--;
[0108] M is --(CR.sup.1R.sup.2)--;
[0109] X is --C(H)--;
[0110] R.sup.3 is H;
[0111] R.sup.9 is H;
[0112] R.sup.10 is H or alkyl;
[0113] R.sup.11 is H or alkyl;
[0114] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00024##
[0115] where Q is
##STR00025##
[0116] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0117] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0118] In an embodiment of a compound of formula I,
[0119] E is --O--;
[0120] A is
##STR00026##
[0121] G is --CH.sub.2--;
[0122] X is --C(H)--;
[0123] R.sup.3 is H;
[0124] R.sup.9 is H;
[0125] R.sup.10 is H or --CH.sub.3--;
[0126] R.sup.11 is H or --CH.sub.3--;
[0127] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00027##
[0128] where Q is
##STR00028##
[0129] B is --CH.dbd.CH--;
[0130] Het is
##STR00029##
and
[0131] W is
##STR00030##
[0132] In another embodiment of a compound of formula I,
[0133] E is --N(H)-- or --N(alkyl)-;
[0134] A is --N(H)--, --N(alkyl)-,
##STR00031##
or --(CR.sup.1R.sup.2)--;
[0135] G is
##STR00032##
or --(CR.sup.1R.sup.2)--;
[0136] M is --(CR.sup.1R.sup.2)--;
[0137] X is --C(H)--;
[0138] R.sup.3 is H;
[0139] R.sup.9 is H;
[0140] R.sup.10 is H or alkyl;
[0141] R.sup.11 is H or alkyl;
[0142] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00033##
[0143] where Q is
##STR00034##
[0144] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0145] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0146] In another embodiment of a compound of formula I,
[0147] E is --N(H)-- or --N(alkyl)-;
[0148] A is
##STR00035##
[0149] G is --CH.sub.2--;
[0150] X is --C(H)--;
[0151] R.sup.3 is H;
[0152] R.sup.9 is H;
[0153] R.sup.10 is H or --CH.sub.3--;
[0154] R.sup.11 is H or --CH.sub.3--;
[0155] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00036##
[0156] where Q is
##STR00037##
[0157] B is --CH.dbd.CH--;
[0158] Het is
##STR00038##
and
[0159] W is
##STR00039##
[0160] In another embodiment of a compound of formula
[0161] E is
##STR00040##
[0162] A is --N(H)-- or --N(alkyl)-;
[0163] G is --N.dbd.;
[0164] M is --(CR.sup.1R.sup.2)--;
[0165] X is --C(H)--;
[0166] R.sup.3 is H;
[0167] R.sup.9 is H;
[0168] R.sup.10 is H or alkyl;
[0169] R.sup.11 is H or alkyl;
[0170] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00041##
[0171] where Q is
##STR00042##
[0172] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0173] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0174] In another embodiment of a compound of formula I,
[0175] A is --N(H)-- or --N(CH.sub.3)--;
[0176] R.sup.10 is H or --CH.sub.3:
[0177] R.sup.11 is H or --CH.sub.3;
[0178] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00043##
[0179] where Q is
##STR00044##
[0180] B is --CH.dbd.CH--;
[0181] Het is
##STR00045##
and
[0182] W is
##STR00046##
[0183] In another embodiment of a compound of formula I,
[0184] E is --O--;
[0185] A is --O--,
##STR00047##
or --(CR.sup.1R.sup.2)--;
[0186] G is
##STR00048##
or --(CR.sup.1R.sup.2)--;
[0187] M is --(CR.sup.1R.sup.2)--;
[0188] X is --C(H)--;
[0189] R.sup.3 is H;
[0190] R.sup.9 is H;
[0191] R.sup.10 is H or alkyl;
[0192] R.sup.11 is H or alkyl;
[0193] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00049##
[0194] where Q is
##STR00050##
[0195] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0196] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0197] In an embodiment of a compound of formula I,
E is --O--;
[0198] A is
##STR00051##
[0199] G is --CH(CH.sub.3)--;
[0200] X is --C(H)--;
[0201] R.sup.3 is H;
[0202] R.sup.9 is H;
[0203] R.sup.10 is H or --CH.sub.3--;
[0204] R.sup.11 is H or --CH.sub.3--;
[0205] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00052##
[0206] where Q is
##STR00053##
[0207] B is --CH.dbd.CH--;
[0208] Het is
##STR00054##
and
[0209] W is
##STR00055##
[0210] For compounds of Formula I, further preferred embodiments
are as follows:
##STR00056##
[0211] In an embodiment of a compound of formula I where:
##STR00057##
is
##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062##
[0212] In an embodiment of a compound of formula I,
[0213] R.sup.3 is absent or R.sup.3 is H;
[0214] R.sup.9 is H;
[0215] R.sup.10 is H or alkyl;
[0216] R.sup.11 is H or alkyl;
[0217] R.sup.32 is H or alkyl;
[0218] R.sup.33 is H or alkyl; or R.sup.32 and R.sup.33 are
combined to form a ring structure Q, below
##STR00063##
[0219] where Q is
##STR00064##
[0220] B is --CH.dbd.CH--
[0221] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0222] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0223] In an additional embodiment of a compound of formula I,
[0224] R.sup.3 is H;
[0225] R.sup.9 is H;
[0226] R.sup.10 is H or --CH.sub.3--;
[0227] R.sup.11 is H or --CH.sub.3--;
[0228] R.sup.32 is H or --CH.sub.3--;
[0229] R.sup.33 is H or --CH.sub.3--;
[0230] Het is
##STR00065##
and
[0231] W is
##STR00066##
[0232] In an embodiment of a compound of formula I,
[0233] R.sup.3 is absent or R.sup.3 is H;
[0234] R.sup.9 is H;
[0235] R.sup.10 is H;
[0236] R.sup.11 is H;
[0237] R.sup.32 and R.sup.33 are combined to form a ring structure
Q, below
##STR00067##
[0238] where Q is
##STR00068##
[0239] R.sup.13 is (--CH.sub.2).sub.n6NHC(O)OR.sup.16b;
[0240] R.sup.16b is alkyl;
[0241] B is --CH.dbd.CH--
[0242] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0243] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0244] In an embodiment of a compound of formula I,
[0245] R.sup.13 is --NHC(O)OCH.sub.2CH.sub.3;
[0246] Het is
##STR00069##
and
[0247] W is
##STR00070##
[0248] In an embodiment of a compound of formula
[0249] E is --O--, --N(H)-- or --N(alkyl)-;
[0250] A is --N(H)--, --N(alkyl)-, --O--,
##STR00071##
or --(CR.sup.1R.sup.2)--;
[0251] G is --N.dbd.,
##STR00072##
or --(CR.sup.1R.sup.2)--;
[0252] M is --(CR.sup.1R.sup.2)--;
[0253] X is --C(H)--;
[0254] R.sup.3 is H;
[0255] R.sup.9 is H;
[0256] R.sup.10 is H or alkyl;
[0257] R.sup.11 is H or alkyl;
[0258] R.sup.32 is H or alkyl;
[0259] R.sup.33 is H or alkyl;
[0260] or R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below
##STR00073##
[0261] where Q is
##STR00074##
[0262] B is CR.sup.12.dbd.CR.sup.12a--
[0263] R.sup.12 and R.sup.12a are H;
[0264] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0265] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0266] In an embodiment of a compound of formula I,
[0267] E is --O--, --N(H)-- or --N(alkyl)-;
[0268] A is --N(H)--, --N(alkyl)-, --O--,
##STR00075##
or --(CR.sup.1R.sup.2)--;
[0269] G is --N.dbd.,
##STR00076##
--CH.sub.2-- or --C(CH.sub.3)--;
[0270] X is --C(H)--;
[0271] R.sup.3 is H;
[0272] R.sup.9 is H;
[0273] R.sup.10 is H or --CH.sub.3--;
[0274] R.sup.11 is H or --CH.sub.3--;
[0275] R.sup.32 is H or --CH.sub.3;
[0276] R.sup.33 is H or --CH.sub.3;
[0277] or R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below
##STR00077##
[0278] where Q is
##STR00078##
[0279] B is --CH.dbd.CH--;
[0280] Het is
##STR00079##
and
[0281] W is
##STR00080##
[0282] In an embodiment of a compound of formula I,
[0283] E is
##STR00081##
[0284] A is --N(H)-- or --N(alkyl)-;
[0285] G is --N.dbd.;
[0286] M is --(CR.sup.1R.sup.2)--;
[0287] X is --C(H)--;
[0288] R.sup.3 is H;
[0289] R.sup.9 is H;
[0290] R.sup.10 is H or alkyl;
[0291] R.sup.11 is H or alkyl;
[0292] R.sup.32 is H or --CH.sub.3;
[0293] R.sup.33 is H or --CH.sub.3;
[0294] or R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below
##STR00082##
[0295] where Q is
##STR00083##
and R.sup.13 is (--CH.sub.2).sub.n6NHC(O)OR.sup.16b;
[0296] Het is aryl, aryl substituted by W, heteroaryl or heteroaryl
substituted by W; and
[0297] W is aryl or aryl substituted with the 1 to 3 moieties
comprising halogen, alkyl, --CF.sub.3, --CN, --OH or --O-alkyl.
[0298] In an embodiment of a compound of formula I,
[0299] A is --N(H)-- or --N(CH.sub.3)--;
[0300] R.sup.10 is H or --CH.sub.3;
[0301] R.sup.11 is H or --CH.sub.3;
[0302] R.sup.32 is H or --CH.sub.3;
[0303] R.sup.33 is H or --CH.sub.3;
[0304] or R.sup.32 and R.sup.33 are combined to form a ring
structure Q, below
##STR00084##
[0305] where Q is
##STR00085##
and R.sup.13 is --NHC(O)OCH.sub.2CH.sub.3;
[0306] B is --CH.dbd.CH--;
[0307] Het is
##STR00086##
and
[0308] W is
##STR00087##
[0309] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
[0310] "Patient" includes both human and animals.
[0311] "Subject" includes both mammals and non-mammalian
animals.
[0312] "Mammal" means humans and other mammalian animals.
[0313] The following definitions apply regardless of whether a term
is used by itself or in combination with other terms, unless
otherwise indicated. Therefore, the definition of "alkyl" applies
to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl",
"haloalkyl", "alkoxy", etc.
[0314] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl,
nonyl, decyl, fluoromethyl, trifluoromethyl and
cyclopropylmethyl.
[0315] "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which
the aryl and alkyl are as previously described. Preferred aralkyls
comprise a lower alkyl group. Non-limiting examples of suitable
aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl.
The bond to the parent moiety is through the alkyl.
[0316] "Alkylaryl" means an alkyl-aryl- group in which the alkyl
and aryl are as previously described. Preferred alkylaryls comprise
a lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0317] "Alkenyl" means an aliphatic hydrocarbon group (straight or
branched carbon chain) comprising one or more double bonds in the
chain and which can be conjugated or unconjugated. Useful alkenyl
groups can comprise 2 to about 15 carbon atoms in the chain,
preferably 2 to about 12 carbon atoms in the chain, and more
preferably 2 to about 6 carbon atoms in the chain. The alkenyl
group can be substituted by one or more substituents independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano and alkoxy. Non-limiting examples of suitable
alkenyl groups include ethenyl, propenyl, n-butenyl,
3-methylbut-enyl and n-pentenyl.
[0318] Where an alkyl or alkenyl chain joins two other variables
and is therefore bivalent, the terms alkylene and alkenylene,
respectively, are used.
[0319] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. The term
"substituted alkynyl" means that the alkynyl group may be
substituted by one or more substituents which may be the same or
different, each substituent being independently selected from the
group consisting of alkyl, aryl and cycloalkyl.
[0320] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl, naphthyl, indenyl,
tetrahydronaphthyl and indenyl. "Arylene" means a bivalent phenyl
group, including ortho, meta and para-substitution.
[0321] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, --C(.dbd.N--CN)--NH.sub.2, --C(.dbd.NH)--NH.sub.2,
--C(.dbd.NH)--NH(alkyl), Y.sub.1Y.sub.2NC(O)--,
Y.sub.1Y.sub.2NSO.sub.2-- and --SO.sub.2NY.sub.1Y.sub.2, wherein
Y.sub.1 and Y.sub.2 can be the same or different and are
independently selected from the group consisting of hydrogen,
alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may
also mean a single moiety which simultaneously replaces two
available hydrogens on two adjacent carbon atoms (one H on each
carbon) on a ring system. Examples of such moiety are methylene
dioxy, ethylenedioxy, --C(CH.sub.3).sub.2-- and the like which form
moieties such as, for example:
##STR00088##
[0322] The term "Boc" refers to N-tert-butoxycarbonyl.
[0323] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined above.
Non-limiting examples of suitable monocyclic cycloalkyls include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
the like. Non-limiting examples of suitable multicyclic cycloalkyls
include 1-decalinyl, norbornyl, adamantyl and the like, as well as
partially saturated species such as, for example, indanyl,
tetrahydronaphthyl and the like,
[0324] "Cycloalkenyl" means a non-aromatic mono or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms which contains at least one
carbon-carbon double bond. Preferred cycloalkenyl rings contain
about 5 to about 7 ring atoms. The cycloalkenyl can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined above. Non-limiting
examples of suitable monocyclic cycloalkenyls include
cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
Non-limiting example of a suitable multicyclic cycloalkenyl is
norbornylenyl.
[0325] "Cycloalkylene" refers to a corresponding bivalent ring,
wherein the points of attachment to other groups include all
positional isomers.
[0326] "Dihydroxyalkyl" refers to an alkyl chain substituted by two
hydroxy groups on two different carbon atoms.
[0327] "Fluoroalkyl", "difluoroalkyl" and "trifluoroalkyl" mean
alkyl chains wherein the terminal carbon is substituted by 1, 2 or
3 fluoroatoms, respectively, e.g., --CF.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2CHF.sub.2 or --CH.sub.2CH.sub.2F.
[0328] "Halo" refers to fluorine, chlorine, bromine or iodine
radicals. Preferred are fluoro, chloro or bromo, and more preferred
are fluoro and chloro.
[0329] "Halogen" means fluorine, chlorine, bromine, or iodine.
Preferred are fluorine, chlorine and bromine.
[0330] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination, provided that the rings do not
include adjacent oxygen and/or sulfur atoms. N-oxides of the ring
nitrogens are also included, as well as compounds wherein a ring
nitrogen is substituted by an alkyl group to form a quaternary
amine. Preferred heteroaryls contain about 5 to about 6 ring atoms.
The "heteroaryl" can be optionally substituted by one or more "ring
system substituents" which may be the same or different, and are as
defined herein. The prefix aza, oxa or thia before the heteroaryl
root name means that at least a nitrogen, oxygen or sulfur atom
respectively, is present as a ring atom. A nitrogen atom of a
heteroaryl can be optionally oxidized to the corresponding N-oxide.
Non-limiting examples of suitable heteroaryls include pyridyl,
pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including
N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,
thiazolyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyrimidyl,
furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,
pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,
naphthyridyl (e.g., 1, 5 or 1,7), pyrido[2,3]imidazolyl,
imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl,
benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,
quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,
benzoazaindolyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl,
pyridopyrimidinyl, 7-azaindolyl and the like. The term "heteroaryl"
also refers to partially saturated heteroaryl moieties such as, for
example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl
and 4-pyridyl.
[0331] The term "Het" is exemplified by the single ring, bicyclic
and benzofused heteroaryl groups as defined immediately above. Het
groups are joined to group B by a carbon ring member, e.g., Het is
2-pyridyl, 3-pyridyl or 2-quinolyl. The Het ring can be substituted
on any available ring carbon by a group W; 1 to 4 W substituents
can be present on a Het ring.
[0332] "Heterocyclyl" or "heterocycloalkyl" means a non-aromatic
saturated monocyclic or multicyclic ring system comprising about 3
to about 10 ring atoms, preferably about 5 to about 10 ring atoms,
in which one or more of the atoms in the ring system is an element
other than carbon, for example nitrogen, oxygen or sulfur, alone or
in combination, There are no adjacent oxygen and/or sulfur atoms
present in the ring system. Preferred heterocyclyls contain about 5
to about 6 ring atoms. The prefix aza, oxa or thia before the
heterocyclyl root name means that at least a nitrogen, oxygen or
sulfur atom respectively is present as a ring atom. Any --NH in a
heterocyclyl ring may exist protected such as, for example, as an
--N(Boc), --N(CBz), --N(Tos) group and the like; such protections
are also considered part of this invention. The heterocyclyl can be
optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable monocyclic heterocyclyl rings
include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,3-dioxanyl, 1,4-dioxanyl,
tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl,
lactam, lactone, and the like.
[0333] It should be noted that in hetero-atom containing ring
systems of this invention, there are no hydroxyl groups on carbon
atoms adjacent to a N, O or S, as well as there are no N or S
groups on carbon adjacent to another heteroatom. Thus, for
##STR00089##
there is no --OH attached directly to carbons marked 2 and 5.
[0334] It should also be noted that tautomeric forms such as, for
example, the moieties:
##STR00090##
are considered equivalent in certain embodiments of this
invention.
[0335] The term "heterospirocyclic" refers to a spirocyclic
structure containing 3 to 5 carbon atoms and 1 or 2 heteroatoms
selected from the group consisting of N, S and O, provided that the
heteroatoms are not adjacent.
[0336] "Alkylamino" means an alkyl-amino group in which the alkyl
group is as previously described. The bond to the parent moiety is
through the amino.
[0337] "Alkylaminoalkyl" means an alkyl-amino-alkyl group in which
the alkyl groups are as previously described. The bond to the
parent moiety is through the alkyl.
[0338] "Alkylcycloalkylalkyl" means an alkyl-cycloalkyl-alkyl group
in which the alkyl and cycloalkyl groups are as previously
described. The bond to the parent moiety is through the alkyl.
[0339] "Alkylheteroaryl" means an alkyl-heteroaryl group in which
the alkyl and heteroaryl groups are as previously described. The
bond to the parent moiety is through the heteroaryl.
[0340] "Alkylheterocycloalkyl" means an alkyl-heterocycloalkyl
group in which the alkyl and heterocycloalkyl groups are as
previously described. The bond to the parent moiety is through the
heterocycloalkyl group.
[0341] "Alkoxyalkyloxyalkyl" means an alkoxy-alkyl-O-alkyl group in
which the alkoxy and alkyl groups are as previously described. The
bond to the parent moiety is through the alkyl group.
[0342] "Alkynylalkyl" means an alkynyl-alkyl- group in which the
alkynyl and alkyl are as previously described. Preferred
alkynylalkyls contain a lower alkynyl and a lower alkyl group, The
bond to the parent moiety is through the alkyl. Non-limiting
examples of suitable alkynylalkyl groups include
propargylmethyl.
[0343] "Habalkyl" means a halo-alkyl- group in which the alkyl
group is as previously described. The bond to the parent moiety is
through the alkyl. Non-limiting examples of suitable haloalkyl
groups include fluoromethyl and difluoromethyl.
[0344] "Heteroaralkyl" or "heteroarylalkyl" means a
heteroaryl-alkyl- group in which the heteroaryl and alkyl are as
previously described. Preferred heteroaralkyls contain a lower
alkyl group. Non-limiting examples of suitable aralkyl groups
include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the
parent moiety is through the alkyl.
[0345] "Heteroarylalkenyl" means a heteroaryl-alkenyl group in
which the heteroaryl and alkenyl are as previously described.
Preferred heteroarylalkenyl contain a lower alkenyl group. The bond
to the parent moiety is through the alkenyl group.
[0346] "Heterocyclylalkyl" or "heterocycloalkylalkyl" means a
heterocyclyl-alkyl group in which the heterocyclyl and alkyl groups
are as previously described. The bond to the parent moiety is
through the alkyl group.
[0347] "Heterocycloalkyloxy" means a heterocycloalkyl-O-- group in
which the heterocycloalkyl group is as previously described. The
bond to the parent moiety is through the ether atom.
[0348] "Heteroarylalkoxyalkyl" means a heteroaryl-alkoxyalkyl group
in which the heteroaryl and alkoxyalkyl groups are as described
above. The bond to the parent moiety is through the alkyl
group.
[0349] "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0350] "Acyl" means an H--C(O)--, alkyl-C(O)-- or
cycloalkyl-C(O)--, group in which the various groups are as
previously described. The bond to the parent moiety is through the
carbonyl. Preferred acyls contain a lower alkyl. Non-limiting
examples of suitable acyl groups include formyl, acetyl and
propanoyl.
[0351] "Aminoalkyl" means an amino-alkyl group in which the alkyl
group is as previously described. The bond to the parent moiety is
through the alkyl.
[0352] "Aroyl" means an aryl-C(O)-- group in which the aryl group
is as previously described. The bond to the parent moiety is
through the carbonyl. Non-limiting examples of suitable groups
include benzoyl and 1-naphthoyl.
[0353] "Alkenyloxy" means an alkenyl-O-- group in which the alkenyl
group is as previously described. The bond to the parent moiety is
through the ether oxygen.
[0354] "Alkynyloxy" means an alkynyl-O-- group in which the alkenyl
group is as previously described. The bond to the parent moiety is
through the ether oxygen.
[0355] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and
n-butoxy. The bond to the parent moiety is through the ether
oxygen.
[0356] "Aralkoxy" or "arylalkoxy" means an aralkyl-O-- group in
which the aralkyl group is as previously described. The bond to the
parent moiety is through the oxygen atom.
[0357] "Alkoxyalkyl" or "alkyloxyalkyl" means an alkyl-O-alkyl
group in which the alkyl and alkyl groups are as previously
described. Non-limiting examples of suitable alkyloxyalkyl groups
include methoxymethyl and ethoxymethyl. The bond to the parent
moiety is through the alkyl group.
[0358] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0359] "Aryloxyalkyl" means an aryl-O-alkyl group in which the aryl
and alkyl groups are as previously described. Non-limiting examples
of suitable aryloxyalkyl groups include phenoxymethyl and
naphthoxymethyl. The bond to the parent moiety is through the alkyl
group.
[0360] "Arylalkoxyalkyl" means an aryl-alkoxyalkyl group in which
the aryl and alkoxyalkyl groups are as previously described. The
bond to the parent moiety is through the alkyl group.
[0361] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl
group is as previously described. Non-limiting examples of suitable
aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
The bond to the parent moiety is through the ether oxygen.
[0362] "Arylalkenyl" means an aryl-alkenyl- group in which the aryl
and alkenyl groups are as previously described. The bond to the
parent moiety is through the alkenyl.
[0363] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0364] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Non-limiting examples of suitable
arylthio groups include phenylthio and naphthylthio. The bond to
the parent moiety is through the sulfur.
[0365] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. Non-limiting example of a
suitable aralkylthio group is benzylthio. The bond to the parent
moiety is through the sulfur.
[0366] "Alkoxycarbonyl" means an alkyl-O--CO-- group. Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl
and ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0367] "Aryloxycarbonyl" means an aryl-O--C(O)-- group.
Non-limiting examples of suitable aryloxycarbonyl groups include
phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent
moiety is through the carbonyl.
[0368] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group.
Non-limiting example of a suitable aralkoxycarbonyl group is
benzyloxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0369] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-- group. Preferred
groups are those in which the alkyl group is lower alkyl. The bond
to the parent moiety is through the sulfonyl.
[0370] "Arylsulfonyl" means an aryl-S(O.sub.2)-- group. The bond to
the parent moiety is through the sulfonyl.
[0371] "Cycloalkenyloxy" means a cycloalkenyl-O-- group in which
the cycloalkenyl group is as previously described. The bond to the
parent moiety is through the ether atom.
[0372] "Cycloalkylyalkyl" means a cycloalkyl-alkyl group in which
the cycloalkyl and alkyl groups are as previously described. The
bond to the parent moiety is through the alkyl group.
[0373] "Cycloalkyloxy" or "cycloalkoxy" means a cycloalkyl-O--
group in which the cycloalkyl group is as previously described. The
bond to the parent moiety is through the ether atom.
[0374] "Cycloalkyloxyalkyl" means a cycloalkyl-O-- alkyl group in
which the cycloalkyl and alkyl groups are as previously described.
The bond to the parent moiety is through the alkyl group.
[0375] "Haloalkoxyalkyl" means a halo alkoxyalkyl group in which
the alkoxyalkyl group is as previously described. The bond to the
parent moiety is through the alkyl group.
[0376] "Heterocyclylalkoxyalkyl" means a heterocyclyl-alkoxyalkyl
group in which the alkoxyalkyl group is as previously described.
The bond to the parent moiety is through the alkyl group.
[0377] The optional double bond represented by means that at least
a single bond must be present, but that a double bond can be
present; when the double bond is present, R.sup.10 is absent.
[0378] When R.sup.4 and R.sup.5 join to form a ring with the
nitrogen to which they are attached, the rings formed are
1-pyrrolidinyl, 1-piperidinyl and 1-piperazinyl, wherein the
piperazinyl ring may also be substituted at the 4-position nitrogen
by a group R.sup.7.
[0379] The above statements, wherein, for example, R.sup.4 and
R.sup.5 are said to be independently selected from a group of
substituents, means that R.sup.4 and R.sup.5 are independently
selected when attached to the same nitrogen, but also that where an
R.sup.4 or R.sup.5 variable occurs more than once in a molecule,
those occurrences are independently selected. Similarly, each
occurrence of R.sup.13 or R.sup.14 is independent of any other
R.sup.13 or R.sup.14 in the same Q ring. Those skilled in the art
will recognize that the size and nature of the substituent(s) will
affect the number of substituents which can be present.
[0380] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound` or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0381] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties.
[0382] The term "isolated" or "in isolated form" for a compound
refers to the physical state of said compound after being isolated
from a synthetic process or natural source or combination thereof.
The term "purified" or "in purified form" for a compound refers to
the physical state of said compound after being obtained from a
purification process or processes described herein or well known to
the skilled artisan, in sufficient purity to be characterizable by
standard analytical techniques described herein or well known to
the skilled artisan.
[0383] The structure in the compound of formula I, represents an
optional double bond, the dotted line is a bond or no bond,
resulting in a double bond or a single bond, as permitted by the
valency requirement; with the proviso that R.sup.3 is absent when
the carbon to which R.sup.3 would be attached is part of a double
bond.
[0384] It should also be noted that any carbon as well as
heteroatom with unsatisfied valences in the text, schemes, examples
and Tables herein is assumed to have the sufficient number of
hydrogen atom(s) to satisfy the valences.
[0385] When a functional group in a compound is termed "protected",
this means that the group is in modified form to preclude undesired
side reactions at the protected site when the compound is subjected
to a reaction. Suitable protecting groups will be recognized by
those with ordinary skill in the art as well as by reference to
standard textbooks such as, for example, T. W. Greene et al,
Protective Groups in organic Synthesis (1991), Wiley, New York.
[0386] When any variable (e.g., aryl, heterocycle, R.sup.2, etc.)
occurs more than one time in any constituent or in Formula I, its
definition on each occurrence is independent of its definition at
every other occurrence.
[0387] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0388] Prodrugs, solvates and co-crystals of the compounds of the
invention are also contemplated herein. The term "prodrug", as
employed herein, denotes a compound that is a drug precursor which,
upon administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of Formula I or
a salt and/or solvate thereof. A discussion of prodrugs is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
(1987) 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, (1987) Edward B. Roche, ed., American
Pharmaceutical Association and Pergamon Press, both of which are
incorporated herein by reference thereto.
[0389] "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. "Hydrate" is a
solvate wherein the solvent molecule is H.sub.2O.
[0390] A co-crystal is a crystalline superstructure formed by
combining an active pharmaceutical intermediate with an inert
molecule that produces crystallinity to the combined form.
Co-crystals are often made between a dicarboxlyic acid such as
fumaric acid, succinic acid etc. and a basic amine such as the one
represented by compound I of this invention in different
proportions depending on the nature of the co-crystal. (Rmenar, J.
F. et. al. J Am, Chem. Soc. 2003, 125, 8456).
[0391] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound or a composition of the
present invention effective as thrombin receptor antagonists and
thus producing the desired therapeutic, ameliorative, inhibitory or
preventative effect.
[0392] The compounds of Formula I can form salts which are also
within the scope of this invention. Reference to a compound of
Formula I herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula I contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, although other salts are also useful. Salts of the
compounds of the Formula I may be formed, for example, by reacting
a compound of Formula I with an amount of acid or base, such as an
equivalent amount, in a medium such as one in which the salt
precipitates or in an aqueous medium followed by
lyophilization.
[0393] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates,) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by P. Stahl et al., Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:
Wiley-VCH; S. Berge at al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson at al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto.
[0394] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0395] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0396] Compounds of Formula I, and salts, solvates, co-crystals and
prodrugs thereof, may exist in their tautomeric form (for example,
as an amide or imino ether). All such tautomeric forms are
contemplated herein as part of the present invention.
[0397] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates, co-crystals and prodrugs of the compounds as
well as the salts and solvates, co-crystals of the prodrugs), such
as those which may exist due to asymmetric carbons on various
substituents, including enantiomeric forms (which may exist even in
the absence of asymmetric carbons), rotameric forms, atropisomers,
and diastereomeric forms, are contemplated within the scope of this
invention, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds
of the invention may, for example, be substantially free of other
isomers, or may be admixed, for example, as racemates or with all
other, or other selected, stereoisomers. The chiral centers of the
present invention can have the S or R configuration as defined by
the IUPAC 1974 Recommendations. The use of the terms "salt",
"solvate" "prodrug" and the like, is intended to equally apply to
the salt, solvate and prodrug of enantiomers, stereoisomers,
rotamers, tautomers, positional isomers, racemates or prodrugs of
the inventive compounds.
[0398] Polymorphic forms of the compounds of Formula I, and of the
salts, solvates, co-crystals and prodrugs of the compounds of
Formula I, are intended to be included in the present
invention.
[0399] The compounds according to the invention have
pharmacological properties; in particular, the compounds of Formula
I can be nor-seco himbacine derivatives useful as thrombin receptor
antagonists.
[0400] Compounds of the invention have at least one asymmetrical
carbon atom and therefore all isomers, including enantiomers,
stereoisomers, rotamers, tautomers and racemates of the compounds
of Formula (I) (where they exist) are contemplated as being part of
this invention. The invention includes d and I isomers in both pure
form and in admixture, including racemic mixtures. Isomers can be
prepared using conventional techniques, either by reacting
optically pure or optically enriched starting materials or by
separating isomers of a compound of Formula I. Isomers may also
include geometric isomers, e.g., when a double bond is present.
Polymorphous forms of the compounds of Formula (I), whether
crystalline or amorphous, also are contemplated as being part of
this invention.
[0401] Those skilled in the art will appreciate that for some of
the compounds of Formula I, one isomer will show greater
pharmacological activity than other isomers.
[0402] Typical preferred compounds of the present invention have
the following stereochemistry:
##STR00091##
with compounds having that absolute stereochemistry being more
preferred.
[0403] Those skilled in the art will appreciate that for some
compounds of Formula I, one isomer will show greater
pharmacological activity than other isomers.
[0404] Compounds of the present invention in which are generally
prepared by processes in accordance with the following.
[0405] Some of the following below compounds, intermediates and
processes, can be practiced by the methods as disclosed in any of
U.S. Pat. No. 6,063,847, U.S. Pat. No. 6,326,380, U.S. Pat. No.
6,645,987, U.S. Ser. No. 10/271,715, all of which are incorporated
herein by reference
[0406] Following are examples of preparing starting materials and
compounds of formula I. In the procedures, the following
abbreviations are used: [0407] rt room temperature [0408] THF
tetrahydrofuran [0409] Et.sub.2O ethyl ether [0410] Me methyl
[0411] Et ethyl [0412] EtOAc ethyl acetate [0413] BnOCH.sub.2Cl
benzylchloromethylether [0414] BuLi Butyl Lithium [0415] DBAD
Di-tert-butyl azodicarboxylate [0416] DCE 1,2-dichloroethane [0417]
DCM Dichloromethane [0418] DMF N, N-Dimethylformamide [0419] DMSO
Methyl sulfoxide [0420] HATU hexafluorophosphate [0421] HOBT or
HOBt Hydroxybezotriazole [0422] KHMDS Potassium
bis(trimethylsilyl)amide [0423] LiHMDS or LHMDS: Lithium
bis(trimethylsilyl)amide [0424] NaB(O.sub.2CCH.sub.3).sub.3H Sodium
triacetoxyborohydride [0425] PhSeBr Phenyl selenium bromide [0426]
PS Polymer supported [0427] PS-EDC Polymer supported dimethyl
aminopropyl ethylcarbodiimide hydrochloride [0428] PS-NCO Polymer
supported isocyanate [0429] PS-Tris-NH.sub.2 Polymer supported
trisamine [0430] TFA Trifluoroacetic acid [0431] Ti(OiPr).sub.4
titanium isopropoxide; [0432] TLC thin layer chromatography [0433]
TMSI Trimethylsilyl iodide or iodotrimethylsilane [0434] TEMPO
2,2,6,6-Tetramethyl-1-piperidinyloxy, free radical [0435] DIBAL,
DIBALH Diisobutylaluminum hydride [0436] TIPSOTf Triisopropylsilyl
trifluoromethanesulfanate [0437] DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene
Synthesis
[0438] Lactones such as 4 and 5 can be prepared from the ketone 2
as described in scheme 1. The ketone was alkylated with tert-butyl
bromoacetate to provide intermediate 3 which was reduced with
sodium borohydride then cyclized to provide the cis and trans
lactams 4 and 5.
##STR00092## ##STR00093##
Preparation of 2
[0439] To a solution of 1 (9.0 g, 23.3 mmol) (see U.S. Patent
2004/0152736 A1 for the preparation of 1) in 150 ml THF at
0.degree. C. was added LHMDS as a 1M solution in THF (35 ml, 35
mmol, 1.5 eq.). The mixture was stirred for 30 min. then evacuated
and filled with oxygen using a balloon. The mixture was stirred
under the oxygen atmosphere for 30 min at 0.degree. C. and 1 hr at
rt. The reaction was quenched by the addition of aqueous sodium
sulfite, stirred for 1 hr and extracted with ethyl acetate. The
crude product obtained was purified by silica gel chromatography to
obtain 300 mg of 2 as a minor product.
[0440] MS: 331.1 (MH.sup.+)
Preparation of 3
[0441] To a solution of 2 (160 mg, 0.48 mmol) in 5 ml THF at
0.degree. C. was added a 1M solution of LHMDS in THF (0.58 ml, 058
mmol, 1.2 eq) and after stirring for 10 min, tert-buytl
bromoacetate was added. The mixture was stirred overnight while
allowing warming to rt. It was quenched by the addition of aqueous
ammonium chloride, extracted with ethyl acetate and the crude
product was purified by preparative TLC using 30% ethyl acetate in
hexanes to provide 105 mg of 3.
Preparation of 4 and 5
[0442] To a solution of 3 (105 mg, 0.24 mmol) in 2 ml methanol at
0.degree. C. was added NaBH.sub.4 (9 mg, 0.24 mmol, 1.0 eq.) and
stirred for 15 min. The reaction was quenched by the addition of
aqueous ammonium chloride and extracted with ethyl acetate to give
80 mg of crude product. To a flask containing 55 mg of this crude
product in 0.5 ml dichloromethane was added 0.5 ml of
trifluoroacetic acid and stirred for 2 hr at rt. The solution was
concentrated to dryness and the residue was taken in
dichloromethane and washed with water followed by brine, dried over
MgSO.sub.4, concentrated and purified by preparative TLC using 30%
ethyl acetate in hexanes to provide 14 mg of 4 and 24 mg of 5.
[0443] MS for 4: 373.1 (MH.sup.+)
[0444] MS for 5: 373.1 (MH.sup.+)
[0445] An alternate approach to the preparation of these types of
compounds is described in scheme 2. Carboxylic acid 6 was converted
to the aldehyde 8 via the alcohol 7. Horner-Wordsworth reaction
with phosphonate 9 gave the vinyl pyridine 10 which was
.alpha.-hydroxylated to 11. Reduction of the lactone to the lactol
followed by reaction with Dess-Martin periodinane reagent gave
formate 13 which under basic conditions gave the ketone 14.
Alkylation with tert-butyl bromoacetate gave intermediate 15 which
was reduced to the axial alcohol with L-selectride and cyclized to
the lactone 16 under acidic conditions. Suzuki coupling of 16 gave
the target compounds 17-20.
##STR00094## ##STR00095## ##STR00096##
Preparation of 7
[0446] To a solution of 6 (30 g, 0119 mol) (see U.S. Pat. No.
6,063,847 for the preparation of 6) in 400 ml dichloromethane was
added oxalyl chloride (21 ml, 0.241 mol, 2 eq.) followed by DMF
(275 .mu.l, 3.55 mmol, 5 mol %). The mixture was stirred for 2 hr,
concentrated and evaporated with toluene to provide the acid
chloride. This was dissolved in 500 ml THF, cooled to 0.degree. C.,
added lithium tri-ter-butoxyaluminohydride (76 g, 0.299 mol, 2.5
eq.) and the mixture was stirred for 2 hr, It was diluted with
water, acidified with HCl, extracted with ethyl acetate to provide
21.6 g of 7.
Preparation of 8
[0447] To a solution of 7 (12.0 g, 50.4 mmol) in 200 ml
dichloromethane at 0.degree. C. was added
2,2,6,6-tetramethylpiperidinooxy (160 mg, 1.02 mmol, 2 mol %) and a
solution of potassium bromide (600 mg, 5.04 mmol, 0.1 eq.) in 10 ml
water. To this mixture was added drop by drop Clorox solution (92
g, .about.6.15% NaOCl content) saturated with solid NaHCO.sub.3.
After the addition was complete, the mixture was stirred for 20
min, organic layer separated and the aqueous layer extracted with
dichloromethane. The combined organic layer was washed with aq.
Na.sub.2S.sub.2O.sub.3, brine, dried over MgSO.sub.4, filtered and
concentrated to provide 12 g of 8 as a resin.
Preparation of 10.
[0448] To a solution of 9 (20 g, 65 mmol) (see U.S. Patent
2004/0152736 A1 for the preparation of 9) in 200 ml THF at
0.degree. C. was added a 1M solution of LHMDS in THF (65 ml, 65
mmol) and the mixture stirred for 30 min at 0.degree. C. To this
was added Ti(O'Pr).sub.4 (22.3 ml, 75.5 mmol) followed by a
solution of aldehyde 8 (12 g) in 50 ml THF. The mixture was stirred
for 15 min at 0.degree. C. and 30 min at rt then quenched with aq.
NH.sub.4Cl. Ethyl acetate extraction followed by chromatographic
purification using 0% to 15% ethyl acetate-hexanes gave 13 g of
10.
Preparation of 11
[0449] To a solution of 10 (3.3 g, 8.46 mmol) in 50 ml THF at
0.degree. C. was added a 1M solution of LHMDS in THF (12.7 ml, 12.7
mmol, 1.5 eq.) and stirred for 30 min. The flask was evacuated and
filled with oxygen and stirred under the oxygen atmosphere for 1 hr
at rt. It was quenched by the addition of aq. Na.sub.2SO.sub.3,
stirred for 30 min. extracted with ethyl acetate and purified by
chromatography using 0% to 20% ethyl acetate-hexanes to provide 3 g
of 11.
[0450] MS: 406.1 (MH.sup.+)
Preparation of 12
[0451] To a solution of 11 (42 g, 10.3 mmol) in 75 ml
dichloromethane at -78.degree. C. was added a 20 wt % solution of
DIBALH in toluene (342 mmol, 41.4 mmol, 4 eq.) and stirred for 1 hr
at -78.degree. C. It was quenched by the addition of aq. potassium
sodium tartrate and extracted with dichloromethane to provide 2.89
g of 12.
[0452] MS: 408.22 (MH.sup.+)
Preparation of 13
[0453] To a solution of 12 (2.89 g, 7.08 mmol) in 50 ml
dichloromethane at rt was added NaHCO.sub.3 (1.2 g, 14.28 mmol, 2
eq.) followed by Dess-Martin periodinane (3.90 g, 9.19 mmol, 1.3
eq.) and the suspension was stirred for 2 hr. The reaction mixture
was diluted with ether and stirred with aq. Na.sub.2S.sub.2O.sub.3
and NaHCO.sub.3 until the two layers became clear. The organic
layer was separated and the aqueous layer was extracted with ether.
The combined organic layer was washed with aq.
Na.sub.2S.sub.2O.sub.3, NaHCO.sub.3 mixture and brine. The solution
was dried over MgSO.sub.4, filtered, concentrated and evaporated to
provide .about.3.0 g of 13.
[0454] MS: 406.2 (MH.sup.+)
Preparation of 14
[0455] A solution of 14 (.about.7.08 mmol) in 50 ml methanol was
stirred with K.sub.2CO.sub.3 (3.9 g, 28.2 mmol, 4 eq.) at rt for 3
hr and diluted with water. It was extracted with ether and the
crude product was chromatographed using 0% to 10% ethyl
acetate--hexanes to provide 1.74 g of 14.
[0456] MS: 334.1 (MH.sup.+)
Preparation of 15
[0457] To a solution of 14 (1.39 g, 4.15 mmol) in 30 ml THF at
0.degree. C. was added a 1M solution of LHMDS in THF (5.0 ml, 5.0
mmol, 1.2 eq.) and stirred for 30 min then added tert-butyl
bromoacetate (0.92 ml, 6.23 mmol, 1.5 eq.) and the mixture stirred
overnight allowing to warm to rt. The solution was diluted with aq.
NH.sub.4Cl, extracted with ethyl acetate and the crude product was
purified by chromatography to provide 920 mg of 15.
[0458] MS: 448.1 (MH.sup.+)
Preparation of 16
[0459] To a solution of 15 (140 mg, 0.31 mmol) in 2.5 ml THF at
-78.degree. C. was added 1M solution of L-selectride in THF (0.63
ml, 0.63 mmol, 2 eq) and the mixture stirred for 1 hr at
-78.degree. C. The reaction was quenched with the addition of 4 ml
trifluoroacetic acid and stirred at rt for 1 hr, concentrated and
suspended in aq. NaHCO.sub.3. It was extracted with ethyl acetate
and purified by chromatography using 0% to 20% ethyl
acetate--hexanes to provide 70 mg of 16.
[0460] MS: 376.1 (MH.sup.+)
Preparation of 17
[0461] A solution of 16 (20 mg, 0.053 mmol), m-fluorophenylboronic
acid (11.2 mg, 0.08 mmol, 1.5 eq.), K.sub.2CO.sub.3 (30 mg, 0.217
mmol, 4 eq.) and Pd(PPh.sub.3).sub.4 (3.1 mg, 2.7 .mu.mol, 5 mol)
in a mixture of 1 ml toluene, 0.5 ml ethanol and 0.3 ml water was
bubbled with argon and heated in a sealed tube at 100.degree. C.
for 1 hr. After aqueous work-up, the crude product was purified by
preparative TLC using 20% ethyl acetate-hexanes to provide 14 mg of
17.
[0462] MS: 392.1 (MH.sup.+)
[0463] Compounds 18, 19 and 20 were prepared using an analogous
procedure.
[0464] MS for 18: 442.1 (MH.sup.+)
[0465] MS for 19: 399.2 (MH.sup.+)
[0466] MS for 20: 399.2 (MH.sup.+)
[0467] The lactam analogs were prepared as described in scheme 3.
Reductive amination of ketone 15 gave a mixture of axial and
equatorial amines 21 and 22. Cleavage of the tert-butyl ester of 21
was achieved with trifluoro acetic acid and the resultant amino
acid was treated with HATU to provide the cis lactam 23. Suzuki
coupling gave 24 which on N-methylation gave 25. Similarly, the
equatorial amine 22 was converted to the trans-lactam 27.
##STR00097## ##STR00098## ##STR00099##
Preparation of 21 and 22
[0468] To a solution of 15 (300 mg, 0.67 mmol), in 5 ml methanol
and 1 ml dichloromethane was added ammonium acetate (515 mg, 6.68
mmol, 10 eq.), 3 .ANG. molecular sieves (.about.600 mg) and sodium
cyanoborohydride (42 mg, 0.668 mmol, 1 eq.) and the mixture stirred
at rt for 2 days. It was poured into aqueous sodium bicarbonate,
extracted with dichloromethane and purified by chromatography using
3% 7N ammonia-methanol solution in dichloromethane to provide 150
mg of 21 and 58 mg of 22.
[0469] MS for 21: 449.1 (MH.sup.+)
[0470] MS for 22: 449.1 (MH.sup.+)
Preparation of 23
[0471] A solution of 21 (150 mg) in 1 ml dichloromethane and 3 ml
trifluoroacetic acid was stirred at rt for 2 hr, concentrated and
evaporated with n-heptane to provide the acid. To a solution of
this product in 4 ml DMF at rt was added triethylamine (0.19 ml,
1.36 mmol, 4 eq.) followed by HATU (255 mg, 0.67 mmol, 2 eq.) and
the mixture was stirred overnight at rt. It was diluted with ethyl
acetate and washed aq. sodium bicarbonate, brine, dried over
MgSO.sub.4, filtered and concentrated. The crude product was
chromatographed with 0% to 80% ethyl acetate--hexanes to provide 55
mg of 23.
[0472] MS: 375.1 (MH.sup.+)
Preparation of 24
[0473] A solution of 23 (55 mg, 0.147 mmol), 3-fluorophenylboronic
acid (31 mg, 0.22 mmol, 1.5 eq.), Pd(PPh.sub.3).sub.4 (8.5 mg, 7.4
.mu.mol, 5 mol %) and K.sub.2CO.sub.3 (81 mg, 0.586 mmol, 4 eq.) in
a mixture of toluene (1 ml), ethanol (0.5 ml) and water (0.3 ml) in
a sealed tube was bubbled with argon and heated at 100.degree. C.
for 5 hr. It was poured into water, extracted with ethyl acetate
and purified by preparative TLC using 3% methanol dichloromethane
mixture to provide 44 mg of 24.
[0474] MS: 391.2 (MH.sup.+)
Preparation of 25
[0475] To a solution of 24 (22 mg, 0.056 mmol) in 1 ml DMF at rt
was added sodium hydride (12 mg of 60% dispersion in mineral oil,
0.30 mmol, 5 eq.) followed by iodomethane (0.026 ml, 0.28 mmol, 5
eq.) and the mixture stirred for 2.5 hr at rt. It was poured into
aq. ammonium chloride, extracted with ethyl acetate and purified by
preparative TLC using 80% ethyl acetate--hexanes to provide 9 mg of
25.
[0476] MS: 405.1 (MH.sup.+)
Preparation of 26
[0477] A solution of 22 (55 mg) in 1 ml dichloromethane and 3 ml
trifluoroacetic acid was stirred at rt for 1 hr, concentrated and
evaporated with n-heptane to provide the acid. To a solution of
this acid in 2 ml DMF was added triethylamine (0.070 ml, 0.50 mmol,
4 eq) followed by HATU (93 mg, 0.25 mmol, 2 eq) and stirred
overnight at rt. It was diluted with ethyl acetate, washed with aq.
sodium bicarbonate, brine, dried over MgSO.sub.4 and purified by
chromatography using 3% methanol-dichloromethane to provide 35 mg
of 26.
[0478] MS: 375.1 (MH.sup.+)
Preparation of 27
[0479] A solution of 22 (35 mg, 0.093 mmol), 3-fluorophenylboronic
acid (20 mg, 0.14 mmol, 1.5 eq.), Pd(PPh.sub.3).sub.4 (6 mg, 5.2
.mu.mol, 6 mol %) and K.sub.2CO.sub.3 (52 mg, 0.38 mmol, 4 eq.) in
a mixture of toluene (1 ml), ethanol (0.5 ml) and water (0.3 ml) in
a sealed tube was bubbled with argon and heated at 100.degree. C.
for 5 hr. It was poured into water, extracted with ethyl acetate
and purified by preparative TLC using 3% methanol dichloromethane
mixture to provide 26 mg of 27.
[0480] MS: 391.2 (MH.sup.+)
[0481] Preparation of phthalazinone type analogs are shown in
scheme 4. Lactone 28 was reduced to the did and the primary alcohol
was protected to provide 29. Dess-Martin oxidation followed by
treatment with 1N HCl gave alcohol 31 which was oxidized to the
carboxylic acid 32. Coupling of this acid with hydrazine gave 33
which on N-methylation gave 34.
##STR00100## ##STR00101## ##STR00102##
Preparation of 30
[0482] To a solution of 28 (2.0 g, 4.39 mmol) (see U.S. Pat. No.
6,063,847 for the preparation of 28) in 20 ml THF at rt was added
1M LiAlH.sub.4 solution in THF (4.4 ml, 4.4 mmol, 1 eq.) and
stirred at rt for 1 hr. It was quenched by the addition of small
amount of ethyl acetate, concentrated under vacuum and poured into
water. The slurry was acidified with dilute sulfuric acid and
extracted 3.times. with dichloromethane. The combined organic layer
was washed with water, aq. sodium bicarbonate, brine, dried over
MgSO.sub.4, filtered and concentrated to provide the diol.
[0483] To a solution of this diol and triethyl amine (0.92 ml, 6.60
mmol, 1.5 eq.) in 30 ml dichloromethane at -40.degree. C. was added
triisopropylsilyl trifluoromethanesulfonate (1.3 ml, 4.84 mmol, 1.1
eq.) and stirred for 1 hr while allowing the solution to warm up to
0.degree. C. The mixture was diluted with ether, washed with aq.
sodium bicarbonate and brine. It was dried over MgSO.sub.4,
filtered and concentrated to provide crude 29.
[0484] To a solution of above crude 29 in 30 ml dichloromethane at
was added NaHCO.sub.3 (1.85 g, 22.02 mmol) and Dess-Martin
periodinane (2.1 g, 5.29 mmol) and stirred for 1 hr. It was diluted
with ether, added aqueous solution of Na.sub.2S.sub.2O.sub.3 and
NaHCO.sub.3, stirred vigorously and the organic layer separated.
The aqueous phase was extracted with ether and the combined organic
layer was washed with brine, dried over MgSO.sub.4, filtered,
concentrated and chromatographed with 0% to 10% ethyl
acetate-hexane to provide 1.83 g of 30.
Preparation of 31
[0485] To a solution of 30 (1.05 g, 1.71 mmol) in 10 ml THF at rt
was added 0.85 ml of con. HCl and the mixture stirred for 2 hr. It
was poured into aq. NaHCO.sub.3 solution and extracted 3.times.
with ethyl acetate. The combined organic layer was washed with
brine, dried over MgSO.sub.4, filtered, concentrated and
chromatographed with 0% to 50% ethyl acetate-hexanes to provide
0.70 g of 31.
[0486] MS: 458.1 (MH.sup.+)
Preparation of 32
[0487] To a solution of 31 (530 mg, 1.16 mmol) in 10 ml
dichloromethane at rt was added NaHCO.sub.3 (195 mg, 2.32 mmol, 2
eq.) and Dess-Martin periodinane (550 mg, 1.39 mmol, 1.2 eq.) and
the mixture was stirred at rt for 2 hr. It was diluted with ether
and stirred vigorously with an aqueous solution of
Na.sub.2S.sub.2O.sub.3 and NaHCO.sub.3 for 30 min. The organic
layer was separated and the aqueous layer was extracted 2.times.
with ether. The combined organic layer was washed with an aqueous
solution of Na.sub.2S.sub.2O.sub.34 and NaHCO.sub.3, brine, dried
over MgSO.sub.4, filtered and concentrated to provide the crude
aldehyde.
[0488] To a solution of this aldehyde in 3 ml THF and 7 ml
acetonitrile was added aqueous hydrogen peroxide solution (0.13 ml
of 30% solution, 1.26 mmol, 1.1 eq) and NaH.sub.2PO.sub.4 (35 mg,
0.29 mmol, 0.25 eq.). To this mixture was added a solution of
NaClO.sub.2 (185 mg of 80% solid, 1.64 mmol, 1.4 eq) in 3 ml water.
After stirring for 1 hr at rt, the solution was diluted with water
and extracted 3.times. with dichloromethane. The combined organic
layer was washed with brine, dried over MgSO.sub.4, filtered and
concentrated to provide 490 mg of 32.
[0489] MS: 472.1 (MH.sup.+)
Preparation of 33
[0490] To a suspension of 32 (0.49 g, 1.04 mmol) in 10 ml
acetonitrile and 5 ml DMF was added HOBt (0.17 g, 1.26 mmol, 1.2
eq) followed by EDCl (0.24 g, 1.25 mmol, 1.2 eq.) and 5 ml
dichloromethane. The solution was stirred for 1 ht at rt then
cooled to 0.degree. C. and transferred to another flask containing
a solution of hydrazine (65 .mu.l, 2.07 mmol, 2 eq.) and
cyclohexene (100 .mu.A) in 5 ml acetonitrile kept at 0.degree. C.
The mixture was stirred for 30 min, diluted with ethyl acetate,
washed 3.times. with aq. NaHCO.sub.3, brine, dried over MgSO.sub.4,
filtered, concentrated and chromatographed with 50% ethyl
acetate-hexanes to provide 280 mg of 33.
[0491] MS: 468.1 (MH.sup.+)
Preparation of 34
[0492] To a solution of 33 (180 mg, 0.39 mmol) in 3 ml DMF at it
was added NaH (23 mg of 60% dispersion in mineral oil, 0.87 mmol,
1.5 eq.) and iodomethane (36 .mu.l, 0.58 mmol, 1.5 eq.). The
mixture was stirred for 3 hr, added aq. ammonium chloride and
extracted 3.times. with ethyl acetate. The combine organic layer
washed 2.times. with water, brine, dried over MgSO.sub.4, filtered,
concentrated and chromatographed with 0% to 25% ethyl
acetate--hexanes to provide 170 mg of 34.
[0493] MS: 482.1 (MH.sup.+)
[0494] Another alternative preparation of isolactone analogs is
presented below. Alcohol 7 was protected as benzyl ether and
.alpha.-oxygenated to provide 42. Dibal reduction followed by
Dess-Martin reaction gave formate 44 which was converted to enone
45. Conjugate addition of cyanide followed by reduction and
hydrolysis gave lactone 47 which was converted to targets 51, 52
and 54.
##STR00103## ##STR00104## ##STR00105##
Preparation of 41
[0495] Sodium hydride (840 mg, 21 mmol) was added to a stirred
solution of 7 (2.0 g, 8.4 mmol) and Bu.sub.4NI (930 mg, 2.6 mmol)
in DMF at 0.degree. C. under N.sub.2. The mixture was stirred for
30 minutes and brought to room temperature. Benzyl bromide (2.5 mL,
21 mmol) was added drop wise to the above mixture and stirred at
room temperature for another 2.5 hours. The mixture was poured into
a sat. NH.sub.4Cl solution and extracted with ethyl ether. The
combined organic extracts were washed with H.sub.2O, brine and
dried over MgSO.sub.4, The crude residue was purified via silica
gel column chromatography (ethyl acetate I Hexane 10:90) to give
compound 41 (2.6 g, 7.9 mmol, 96%).
Preparation of 42
[0496] To a solution of 41 (100 mg, 0.31 mmol) in THF (2 ml) at
0.degree. C. under Argon was added LiHMDS (0.92 mL, 1M in THF
solution). The mixture was brought to room temperature and stirred
for 30 minutes then under oxygen atmosphere for over 2 hours.
Na.sub.2SO.sub.3 (6 mL) was added to the mixture and stirred for 30
minutes. The organic layer was extracted with ethyl acetate and
CH.sub.2Cl.sub.2. The combined extracts were dried over MgSO.sub.4.
The crude product was purified via flash chromatography (ethyl
acetate/Hexane 5:95) and evaporated to give 42 (58 mg, 0.17 mmol,
55%).
Preparation of 43
[0497] To a solution of 42 (647 mg, 1.9 mmol) in CH.sub.2Cl.sub.2
(6 mL) at -78.degree. C. under N.sub.2 was added DIBAL drop wise
and the mixture was slowly brought to room temperature. After 3
hours of stirring the mixture was diluted with ethyl acetate and
poured into sat. sodium potassium tartrate. The organic layer was
extracted with ethyl acetate then CH.sub.2Cl.sub.2. The combined
extracts were dried over MgSO.sub.4 to give crude material 43 (651
mg).
Preparation of 44
[0498] To a solution of 43 (2.42 g, 7.0 mmol) in CH.sub.2Cl.sub.2
(70 mL) at 0.degree. C. under N.sub.2 was added Dess-Martin
periodinane (4.5 g, 10.5 mmol). The mixture was stirred for 1 hour
and slowly brought to room temperature. After 2 hours of stirring,
Sat. Na.sub.2S.sub.2O.sub.3 (100 was added and stirred for 10
minutes then Sat. NaHCO.sub.3 (100 mL) was added. About 45 minutes
of stirring, the organic layer was extracted with ethyl acetate
then CH.sub.2Cl.sub.2. The combined extracts were dried over
MgSO.sub.4 and evaporated to give compound 44 (2.21 g, 6.4 mmol,
92%).
Preparation of 45
[0499] DBU (1.2 ml, 2.61 mmol) was added drop wise to a solution of
44 in toluene (30 mL) and heated at 110.degree. C. for 2 hours. The
mixture was diluted with CH.sub.2Cl.sub.2 and washed with
NaHCO.sub.3 then H.sub.2O. The organic layer was dried over
MgSO.sub.4 and evaporated. The crude residue was purified via flash
chromatography (Ethyl acetate I Hexane, 5:95) to give 45 (1.5 g,
5.0 mmol, 78%).
Preparation of 46
[0500] To a stirring solution of 45 (20 mg, 0.7 mmol) in toluene
(2.0 mL) at room temperature was added diethylaluminum cyanide
(0.31 mL, 0.31 mmol) and stirred for 3 hours. The mixture was
diluted with ethyl acetate and poured into a solution of sat.
sodium potassium tartrate. The organic layer was extracted with
ethyl acetate then CH.sub.2Cl.sub.2. The combined extracts were
dried over MgSO.sub.4 and concentrated. The resulting residue was
purified via flash chromatography (Ethyl acetate/Hexane, 5:95) to
give compound 46 (17 mg, 0.05 mmol, 79%).
Preparation of 47
[0501] Sodium borohydride (755 mg, 19.97 mmol) was added to a
solution of 46 (775 mg, 2.3 mmol) in MeOH (60 mL) and heated at
40.degree. C. for 1.5 hour. After the solution was brought to room
temperature, 5N HCl (75 mL) was added and the mixture heated for
another 4 hours at 90.degree. C. The solution was concentrated to
remove the methanol then extracted with CH.sub.2Cl.sub.2. The
combined extracts were washed with a solution of sat. sodium
potassium tartrate and dried over MgSO.sub.4. The residue was
purified via flash column (Ethyl acetate/Hexane, 5:95) to give 47
(775 mg, 2.4 mmol, 79%).
Preparation of 48
[0502] To a solution of 47 (30 mg, 0.09 mmol) in ethyl acetate/MeOH
(2.0 mL/1.0 mL, 2:1) was added Pd/C (16 mg) and stirred under
hydrogen atmosphere for 6 hours. The mixture was filtered through a
celite pad and concentrated to give crude 48 (29 mg).
Preparation of 49
[0503] To a solution of 48 (29 mg, 0.12 mmol) in CH.sub.2Cl.sub.2
(2.0 mL) at 0.degree. C. was added Dess-Martin periodinane (78 mg,
0.18 mmol) and stirred for 3 hours. A solution of sat.
Na.sub.2S.sub.2O.sub.3 was added to the mixture and stirred for 10
minutes then NaHCO.sub.3 was added. After 40 minutes of stirring,
the organic layer was extracted with ethyl acetate then
CH.sub.2Cl.sub.2 and dried over MgSO.sub.4 to afford compound 14
(20 mg, 0.09 mmol, 75%).
Preparation of 50
[0504] To a solution of 9 (63 mg, 0.20 mmol) in THF (3.0 mL) at
0.degree. C. was added nBuLi (0.08 mL, 0.20 mmol) and stirred for
15 minutes. To this was added a solution of 49 (16 mg, 0.07 mmol)
in THF (3.0 mL) followed by Ti(O.sup.iPr).sub.4 (0.06 mL, 0.20
mmol). The mixture was diluted with ethyl acetate after 4 hours of
stirring and poured into H.sub.2O. It was extracted with ethyl
acetate then CH.sub.2Cl.sub.2, dried over MgSO.sub.4 and the crude
product purified by preparative TLC using 4:6 ethyl acetate-hexanes
to provide 50 (29 mg, 0.07 mmol, .about.100%).
Preparation of 54
[0505] To a solution of 53 (162 mg, 0.50 mmol) in THF (3.0 mL) at
0.degree. C. was added nBuLi (0.20 mL, 0.48 mmol) and stirred for
15 minutes. To this was added a solution of 49 (20 mg, 0.08 mmol)
in THF (3.0 mL), followed by Ti(O.sup.iPr).sub.4 (0.15 mL, 0.50
mmol) and stirred for 4 hours. The reaction mixture was washed with
H.sub.2O, dried over MgSO.sub.4 and evaporated. The residue was
purified via preparative TLC (Ethyl acetate, 100%) to afford
compound 54 (23 mg, 0.06 mmol, 71%).
[0506] MS: m/z 406 [MH.sup.+]
Preparation of 51
[0507] A mixture 50 (17 mg, 0.04 mmol), 2,5-difluorophenylboronic
acid (30 mg, 0.21 mmol) and tetrakis(triphenyl phosphine)palladium
(10 mg) in toluene:H.sub.2O:EtOH (2.0 mL:1.0 mL:0.5 mL) was heated
at reflux under N.sub.2 atmosphere and stirred for 24 hours. After
aqueous work-up, the crude material was purified via preparative
TLC to give 13 mg of 51.
[0508] MS: m/z 406 [MH.sup.+].
[0509] The compound 52 was prepared using a similar procedure.
[0510] MS: m/z 455 [MH.sup.+]
##STR00106## ##STR00107## ##STR00108## ##STR00109##
##STR00110##
[0511] Following the above procedures, the following compounds can
be made:
##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115##
##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120##
##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140##
##STR00141##
[0512] Further, following the above procedures, the following group
of compounds can be made:
##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146##
##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151##
##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156##
##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161##
##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166##
##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171##
##STR00172##
[0513] Further embodiments of the invention encompass the
administration of compounds of Formula I along with at least one
additional agent. The contemplated additional agent is one that
differs in either atomic make up or arrangement from the compounds
of Formula I. Additional agents that can be used in combination
with the novel compounds of this invention include drugs which have
anti-thrombotic, anti-platelet aggregation, antiatherosclerotic,
antirestenotic and/or anti-coagulant activity. Such drugs are
useful in treating thrombosis-related diseases including
thrombosis, atherosclerosis, restenosis, hypertension, angina
pectoris, angiogenesis related disorders, arrhythmia, a
cardiovascular or circulatory disease or condition, heart failure,
myocardial infarction, glomerulonephritis, thrombotic stroke,
thromboembolytic stroke, peripheral vascular diseases, cerebral
ischemia, rheumatoid arthritis, rheumatism, astrogliosis, a
fibrotic disorder of the liver, kidney, lung or intestinal tract,
systemic lupus erythematosus, multiple sclerosis, osteoporosis,
glomerulonephritis, renal disease, acute renal failure, chronic
renal failure, renal vascular homeostasis, renal ischemia, bladder
inflammation, diabetes, diabetic neuropathy, cerebral stroke,
cerebral ischemia, nephritis, cancer, melanoma, renal cell
carcinoma, neuropathy and/or malignant tumors, neurodegenerative
and/or neurotoxic diseases, conditions, or injuries, inflammation,
asthma, glaucoma, macular degeneration, psoriasis, endothelial
dysfunction disorders of the liver, kidney or lung inflammatory
disorders of the lungs and gastrointestinal tract, respiratory
tract disease or condition, radiation fibrosis, endothelial
dysfunction, periodontal diseases or wounds or a spinal cord
injury, or a symptom or result thereof, as well as other disorders
in which thrombin and its receptor play a pathological role.
[0514] Suitable cardiovascular agents are selected from the group
consisting of thromboxane A2 biosynthesis inhibitors; thromboxane
antagonists; adenosine diphosphate inhibitors; cyclooxygenase
inhibitors; angiotensin antagonists; endothelin antagonists;
phosphodiesterase inhibitors; angiotensin converting enzyme
inhibitors; neutral endopeptidase inhibitors; anticoagulants;
diuretics; platelet aggregation inhibitors; and GP IIb/IIIa
antagonists.
[0515] Preferred types of drugs for use in combination with the
novel compounds of this invention are thromboxane A2 biosynthesis
inhibitors, GP IIb/IIIa antagonists, thromboxane antagonists,
adenosine diphosphate inhibitors, cyclooxygenase inhibitors,
angiotensin antagonists, endothelin antagonists, angiotensin
converting enzyme inhibitors, neutral endopeptidase inhibitors,
anticoagulants, diuretics, and platelet aggregation inhibitors.
[0516] In particular, suitable cardiovascular agents are selected
from the group consisting of aspirin, seratrodast, picotamide and
ramatroban, clopidogrel, meloxicam, rofecoxib, celecoxib,
valsartan, telmisartan, candesartran, irbesartran, losartan,
eprosartan, tezosentan, milrinoone, enoximone, captopril,
enalapril, enaliprilat, spirapril, quinapril, perindopril,
ramipril, fosinopril, trandolapril, lisinopril, moexipril,
benazapril, candoxatril, ecadotril, ximelagatran, fondaparin,
enoxaparin, chlorothiazide, hydrochlorothiazide, ethacrynic acid,
furosemide, amiloride, abciximab, eptifibatide, prasugrel and
fragmin.
[0517] Especially preferred for use in the combinations are
aspirin, cangrelor, clopidogrel bisulfate, prasugrel and
fragmin.
[0518] When the invention comprises a combination of a compound of
Formula I and another agent, the two active components may be
co-administered simultaneously or sequentially, or a single
pharmaceutical composition comprising a compound of Formula I and
another agent in a pharmaceutically acceptable carrier can be
administered. The components of the combination can be administered
individually or together in any conventional dosage form such as
capsule, tablet, powder, cachet, suspension, solution, suppository,
nasal spray, etc. The dosage of the cardiovascular agent can be
determined from published material, and may range from 1 to 1000 mg
per dose.
[0519] In this specification, the term "at least one compound of
Formula I" means that one to three different compounds of Formula I
may be used in a pharmaceutical composition or method of treatment.
Preferably one compound of Formula I is used. Similarly, the term
"one or more additional cardiovascular agents" means that one to
three additional drugs may be administered in combination with a
compound of Formula I; preferably, one additional compound is
administered in combination with a compound of Formula I. The
additional agents can be administered sequentially or
simultaneously with reference to the compound of Formula I.
[0520] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g. magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), The Science and Practice of Pharmacy, 20.sup.th
Edition, (2000), Lippincott Williams & Wilkins, Baltimore,
Md.
[0521] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0522] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0523] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0524] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0525] Preferably the compound is administered orally,
[0526] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0527] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 150
mg, preferably from about 1 mg to about 75 mg, more preferably from
about 1 mg to about 50 mg, according to the particular
application.
[0528] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0529] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 1 mg/day to about 300 mg/day,
preferably 1 mg/day to 75 mg/day, in two to four divided doses.
[0530] When separate compounds of Formula I and the other agents
are to be administered as separate compositions, they can be
provided in a kit comprising in a single package, one container
comprising a compound of Formula I in a pharmaceutically acceptable
carrier, and a separate container comprising another cardiovascular
agent in a pharmaceutically acceptable carrier, with the compound
of Formula I and the other agent being present in amounts such that
the combination is therapeutically effective. A kit is advantageous
for administering a combination when, for example, the components
must be administered at different time intervals or when they are
in different dosage forms.
[0531] The activity of the compounds of formula I can be determined
by the following procedures.
In Vitro Testing Procedure for Thrombin Receptor Antagonists:
[0532] Preparation of [.sup.3H]haTRAP
[0533] A(pF-F)R(ChA)(hR)(I.sub.2--Y)--NH.sub.2 (1.03 mg) and 10%
Pd/C (5.07 mg) were suspended in DMF (250 .mu.l) and
diisopropylethylamine (10 .mu.l). The vessel was attached to the
tritium line, frozen in liquid nitrogen and evacuated. Tritium gas
(342 mCi) was then added to the flask, which was stirred at room
temperature for 2 hours. At the completion of the reaction, the
excess tritium was removed and the reacted peptide solution was
diluted with DMF (0.5 ml) and filtered to remove the catalyst. The
collected DMF solution of the crude peptide was diluted with water
and freeze dried to remove the labile tritium. The solid peptide
was redissolved in water and the freeze drying process repeated.
The tritiated peptide ([.sup.3H]haTRAP) was dissolved in 0.5 ml of
0.1% aqueous TFA and purified by HPLC using the following
conditions: column, Vydac.TM. C18, 25 cm.times.9.4 mm ID.; mobile
phase, (A) 0.1% TFA in water, (B) 0.1% TFA in CH.sub.3CN; gradient,
(A/B) from 100/0 to 40/60 over 30 min; flow rate, 5 ml/min;
detection, UV at 215 nm. The radiochemical purity of
[.sup.3H]haTRAP was 99% as analyzed by HPLC. A batch of 14.9 mCi at
a specific activity of 18.4 Ci/mmol was obtained.
Preparation of Platelet Membranes
[0534] Platelet membranes were prepared using a modification of the
method of Natarajan et al. (Natarajan et al, Int. J. Peptide
Protein Res. 45:145-151 (1995)) from 20 units of platelet
concentrates obtained from the North Jersey Blood Center (East
Orange, N.J.) within 48 hours of collection. All steps were carried
out at 4.degree. C. under approved biohazard safety conditions.
Platelets were centrifuged at 100.times.g for 20 minutes at
4.degree. C. to remove red cells. The supernatants were decanted
and centrifuged at 3000.times.g for 15 minutes to pellet platelets.
Platelets were re-suspended in 10 mM Tris-HCl, pH 7.5, 150 mM NaCl,
5 mM EDTA, to a total volume of 200 ml and centrifuged at
4400.times.g for 10 minutes. This step was repeated two additional
times. Platelets were re-suspended in 5 mM Tris-HCl, pH 7.5, 5 mM
EDTA to a final volume of approximately 30 ml and were homogenized
with 20 strokes in a Dounce.TM. homogenizer. Membranes were
pelleted at 41,000.times.g, re-suspended in 40-50 ml 20 mM
Tris-HCl, pH 7.5, 1 mM EDTA, 0.1 mM dithiothreitol, and 10 ml
aliquots were frozen in liquid N.sub.2 and stored at -80.degree. C.
To complete membrane preparation, aliquots were thawed, pooled, and
homogenized with 5 strokes of a Dounce.TM. homogenizer. Membranes
were pelleted and washed 3 times in 10 mM triethanolamine-HCl, pH
7.4, 5 mM EDTA, and re-suspended in 20-25 ml 50 mM Tris-HCl, pH
7.5, 10 mM MgCl.sub.2, 1 mM EGTA, and 1% DMSO. Aliquots of
membranes were frozen in liquid N.sub.2 and stored at -80.degree.
C. Membranes were stable for at least 3 months. 20 units of
platelet concentrates typically yielded 250 mg of membrane protein.
Protein concentration was determined by a Lowry assay (Lowry et a,
J. Biol. Chem., 193:265-275 (1951)).
High Throughput Thrombin Receptor Radioligand Binding Assay
[0535] Thrombin receptor antagonists were screened using a
modification of the thrombin receptor radioligand binding assay of
Ahn et al. (Ahn et al., Mol. Pharmacol, 51:350-356 (1997)). The
assay was performed in 96 well Nunc plates (Cat. No. 269620) at a
final assay volume of 200 .mu.l. Platelet membranes and
[.sup.3H]haTRAP were diluted to 0.4 mg/ml and 22.2 nM,
respectively, in binding buffer (50 mM Tris-HCl, pH 7.5, 10 mM
MgCl.sub.2, 1 mM EGTA, 0.1% BSA). Stock solutions (10 mM in 100%
DMSO) of test compounds were further diluted in 100% DMSO. Unless
otherwise indicated, 10 .mu.l of diluted compound solutions and 90
.mu.l of radioligand (a final concentration of 10 nM in 5% DMSO)
were added to each well, and the reaction was started by the
addition of 100 .mu.l of membranes (40 .mu.g protein/well). The
binding was not significantly inhibited by 5% DMSO. Compounds were
tested at three concentrations (0.1, 1 and 10 .mu.M). The plates
were covered and vortex-mixed gently on a Lab-Line.TM. Titer Plate
Shaker for 1 hour at room temperature. Packard UniFilter.TM. GF/C
filter plates were soaked for at least 1 hour in 0.1%
polyethyleneimine. The incubated membranes were harvested using a
Packard FilterMate.TM. Universal Harvester and were rapidly washed
four times with 300 .mu.l ice cold 50 mM Tris-HCl, pH 7.5, 10 mM
MgCl.sub.2, 1 mM EGTA. MicroScint.TM. 20 scintillation cocktail (25
.mu.l) was added to each well, and the plates were counted in a
Packard TopCount.TM. Microplate Scintillation Counter. The specific
binding was defined as the total binding minus the nonspecific
binding observed in the presence of excess (50 .mu.M) unlabeled
haTRAP. The % inhibition by a compound of [.sup.3H]haTRAP binding
to thrombin receptors was calculated from the following
relationship:
% Inhibition = Total binding - Binding in the presence of a test
compound Total binding - Nonspecific binding .times. 100
##EQU00001##
Materials
[0536] A(pF-F)R(ChA)(hR)Y--NH.sub.2 and
A(pF-F)R(ChA)(hR)(I.sub.2--Y)--NH.sub.2, were custom synthesized by
AnaSpec Inc. (San Jose, Calif.). The purity of these peptides was
>95%. Tritium gas (97%) was purchased from EG&G Mound,
Miamisburg, Ohio. The gas was subsequently loaded and stored on an
IN/US Systems Inc. Trisorber. MicroScint.TM. 20 scintillation
cocktail was obtained from Packard Instrument Co.
Cannabinoid CB.sub.2 Receptor Binding Assay
[0537] Binding to the human cannabinoid CB.sub.2 receptor was
carried out using the procedure of Showalter, et al. (1996, J.
Pharmacol Exp Ther. 278(3), 989-99), with minor modifications. All
assays were carried out in a final volume of 100 ul. Test compounds
were re-suspended to 10 mM in DMSO, then serially diluted in 50 mM
Tris, pH 7.1, 3 mM MgCl.sub.2, 1 mM EDTA, 50% DMSO. Aliquots (10
ul) of each diluted sample were then transferred into individual
wells of a 96-well microtiter plate. Membranes from human CB.sub.2
transfected CHO/Ki cells (Receptor Biology, Inc) were re-suspended
in binding buffer (50 mM Iris, pH 7.1, 3 mM MgCl.sub.2, 1 mM EDTA,
0.1% fatty acid free bovine serum albumin), then added to the
binding reaction (.about.15 ug in 50 ul per assay). The reactions
were initiated with the addition of [.sup.3H] CP-55, 940 diluted in
binding buffer (specific activity=180 Ci/mmol; New England Nuclear,
Boston, Mass.). The final ligand concentration in the binding
reaction was 0.48 nM. Following incubation at room temperature for
2 hours, membranes were harvested by filtration through pretreated
(0.5% polyethylenimine; Sigma P-3143) GF-C filter plates
(Unifilter-96, Packard) using a TomTec.TM. Mach 3U 96-well cell
harvester (Hamden, Conn.). Plates were washed 10 times in 100 ul
binding buffer, and the membranes allowed to air dry. Radioactivity
on membranes was quantitated following addition of Packard
Omniscint.TM. 20 scintillation fluid using a TopCount.TM. NXT
Microplate Scintillation and Luminescence Counter (Packard,
Meriden, Conn.). Non-linear regression analysis was performed using
Prism.TM. 20b. (GraphPad Software, San Diego, Calif.).
[0538] Using the test procedures described above, representative
compounds of formula I were found to have thrombin receptor
IC.sub.50 values (i.e., the concentration at which a 50% inhibition
of thrombin receptor was observed) of 1 to 1000 nM, preferably
1-100 nM, more preferably 1-20 nM. CB.sub.2 Ki values range from 1
to 1000 nM, preferably 1-200 nM, more preferably 1-100 nM.
* * * * *