Aromatic compounds containing basic and acidic termini useful as fibrinogen receptor antagonists

This invention relates to novel compounds containing basic and acidic termini, pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

FIELD OF THE INVENTION 
This invention relates to novel compounds containing basic and acidic 
termini, pharmaceutical compositions containing such compounds, processes 
for preparing such compounds, and to methods of using these compounds, 
alone or in combination with other therapeutic agents, for the inhibition 
of platelet aggregation, as thrombolytics, and/or for the treatment of 
thromboembolic disorders. 
BACKGROUND OF THE INVENTION 
Hemostasis is the normal physiological process in which bleeding from an 
injured blood vessel is arrested. It is a dynamic and complex process in 
which platelets play a key role. Within seconds of vessel injury, resting 
platelets become activated and are bound to the exposed matrix of the 
injured area by a phenomenon called platelet adhesion. Activated platelets 
also bind to each other in a process called platelet aggregation to form a 
platelet plug. This platelet plug can stop bleeding quickly, but it must 
be reinforced by fibrin for long-term effectiveness, until the vessel 
injury can be permanently repaired. 
Thrombosis may be regarded as the pathological condition wherein improper 
activity of the hemostatic mechanism results in intravascular thrombus 
formation. Activation of platelets and the resulting platelet aggregation 
and platelet factor secretion has been associated with different 
pathophysiological conditions including cardiovascular and cerebrovascular 
thromboembolic disorders, for example, the thromboembolic disorders 
associated with unstable angina, myocardial infarction, transient ischemic 
attack, stroke, atherosclerosis, and diabetes. The contribution of 
platelets to these disease processes stems from their ability to form 
aggregates, or platelet thrombi, especially in the arterial wall following 
injury. 
Platelets are known to play an essential role in the maintenance of 
hemostasis and in the pathogenesis of arterial thrombosis. Platelet 
activation has been shown to be enhanced during coronary thrombolysis. 
This can lead to delayed reperfusion and reocclusion. Clinical studies 
with aspirin, ticlopidine, and a monoclonal antibody for platelet 
glycoprotein IIb/IIIa provide biochemical evidence for platelet 
involvement in unstable angina, early stage acute myocardial infarction, 
transient ischemic attack, cerebral ischemia, and stroke. 
Platelets are activated by a wide variety of agonists resulting in platelet 
shape change, secretion of granular contents and aggregation. Aggregation 
of platelets serves to further focus clot formation by concentrating 
activated clotting factors in one site. Several endogenous agonists, 
including adenosine diphosphate (ADP), serotonin, arachidonic acid, 
thrombin, and collagen, have been identified. Because of the involvement 
of several endogenous agonists in activating platelet function and 
aggregation, an inhibitor which acts against all agonists would represent 
a more efficacious antiplatelet agent than currently available 
antiplatelet drugs, which are agonist-specific. 
Current antiplatelet drugs are effective against only one type of agonist; 
these include aspirin, which acts against arachidonic acid; ticlopidine, 
which acts against ADP; thromboxane A.sub.2 synthetase inhibitors or 
receptor antagonists, which act against thromboxane A.sub.2 ; and hirudin, 
which acts against thrombin. 
Recently, a common pathway for all known agonists has been identified, 
namely the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa or 
IIb/IIIa), which is the membrane protein mediating platelet aggregation. A 
recent review of GPIIb/IIIa is provided by Phillips et al. (1991) Cell 65: 
359-362. The development of a GPIIb/IIIa antagonist represents a promising 
new approach for antiplatelet therapy. Recent studies in man with a 
monoclonal antibody for GPIIb/IIIa indicate the antithrombotic benefit of 
a GPIIb/IIIa antagonist. 
There is presently a need for a GPIIb/IIIa-specific antiplatelet agent 
which inhibits the activation and aggregation of platelets in response to 
any agonist. Such an agent should represent a more efficacious 
antiplatelet therapy than the currently available agonist-specific 
platelet inhibitors. 
GPIIb/IIIa on unstimulated platelets does not bind soluble proteins, but 
GPIIb/IIIa in activated platelets is known to bind four soluble adhesive 
proteins, namely fibrinogen, von Willebrand factor, fibronectin, and 
vitronectin. The binding of fibrinogen and von Willebrand factor to 
GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is 
mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is 
common to the adhesive proteins that bind GPIIb/IIIa. 
Several RGD-peptidomimetic compounds have been reported which block 
fibrinogen binding and prevent the formation of platelet thrombi. 
For example, Canadian Patent Application 2,008,311 (Alig et al.) describes 
carboxamides and sulphonamides of the following formula: 
EQU R.sup.1 --A--(W).sub.a --X--(CH.sub.2).sub.b --(Y).sub.c --B--Z--COOR 
wherein: 
A is selected from a radical including phenyl-R.sup.3, pyridyl-R.sup.3, or 
thiophenyl-R.sup.3 ; 
B is selected from a radical including phenyl-R.sup.4, pyridyl-R.sup.4, or 
thiophenyl-R.sup.4 ; 
W is selected from --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, 
--CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.3 --, --CH.sub.2 
CH(CH.sub.3)--, --COCH.sub.2 --, --CH(OH)CH.sub.2 --, or --CH.sub.2 
COCH.sub.2 --; 
X is selected from --CONR.sup.2 --, --NR.sup.2 CO--, --SO.sub.2 NR.sup.2 -- 
or --NR.sup.2 SO.sub.2 --; 
Y is selected from --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 O--, 
--OCH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.dbd.CH--, etc.; 
Z is selected from --OCH.sub.2 --, --NR.sup.6 CH.sub.2 --, --CH.sub.2 
CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.sub.2 --, --CH.dbd.CH--, or 
--C(CH.sub.3).dbd.CH--; 
R is selected from H, lower alkyl, phenyl or phenyl-lower alkyl; 
R.sup.1 is selected from amidino or guanidino; 
R.sup.2 is selected from H, lower alkyl, phenyl-lower-alkyl, etc.; 
R.sup.3 is selected from H, lower alkyl, lower alkoxy, halogen, lower 
carbalkoxy, amino, lower alkylamino, di-lower-alkylamino or amidino; 
R.sup.4 is selected from H, lower alkyl, lower alkoxy, halogen, lower 
carbalkoxy, amino, lower alkylamino, di-lower-alkylamino or a radical 
--Z--COOR or --CH.dbd.CH--(CH.sub.2).sub.n COOR; 
R.sup.6 is selected from H, lower alkyl or benzyl; 
n is selected from an integer of 0-4; 
a and c denote an integer of 0 or 1; 
b is selected from an integer of 0-2, where a and b are 0 when c is 1, and 
c is 0 when a or b is different from zero. 
These compounds are claimed as medicines for the treatment of thrombosis, 
apoplexy, myocardial infarction, inflammations, arteriosclerosis, and 
tumors. 
European Patent Application Publication Number 0,478,363,A2 (Laswell et 
al.) describes sulfonamide fibrinogen IIb/IIIa receptor antagonists of 
formula: 
##STR1## 
wherein: R.sup.1 is selected from a 4 to 8 membered heterocyclic ring 
containing 1-4 heteroatoms; amine, amidine, guanidine, quinuclidine, or 
isoquinuclidine, all of which may be further substituted; 
R.sup.2 and R.sup.3 denote H, aryl, C.sub.1 to C.sub.10 alkyl or 
cycloalkyl, which may be further substituted; 
R.sup.4 is selected from aryl, C.sub.1 to C.sub.10 alkyl, cycloalkyl, 
aralkyl, alkaryl, alkanoyl, alkylamino, alkoxyalkyl, or carboxyalkyl; 
R.sup.5 is selected from a 4 to 8 membered heterocyclic ring with 1-4 
heteroatoms, carboxylic acids, esters, or aminoacid linked carboxamides, 
and prodrugs thereof; 
X, Y, Z are optional substituents selected from N, O, S(O).sub.0-2, 
C.dbd.O, C.dbd.S, CH--OH, CH.dbd.CH, C.tbd.C, a 4 to 8 membered ring with 
0-4 heteroatoms, aryl, amide, or sulfonamide; 
m, n are selected from an integer from 0 to 10; and 
p is selected from an integer from 0 to 3. 
European Patent Application Publication Number 0,478,328 A1 (Egbertson et 
al.) discloses related fibrinogen receptor antagonists wherein the 
SO.sub.2 R.sup.4 group of the compounds in EP 0,478,363,A2 is replaced by 
the R.sup.4 substituent, 
##STR2## 
wherein R.sup.4 is selected from H, aryl, amino acid with amide linkage, 
C.sub.1 to C.sub.10 alkyl, cycloalkyl, aralkyl, alkaryl, alkanoyl, 
alkylamino, alkoxyalkyl, and carboxyalkyl. 
None of the above-cited references disclose or suggest the novel compounds 
of the present invention. 
Compounds of the present invention represent novel structures which bind to 
the glycoprotein IIb/IIIa receptor, thereby preventing fibrinogen from 
binding at its platelet receptor site, leading to efficacy in the 
prevention of blood platelet aggregation and subsequent clotting 
disorders. 
SUMMARY OF THE INVENTION 
This invention provides novel aromatic compounds containing basic and 
acidic termini of Formula I (described below) which are useful as 
antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds 
of the present invention inhibit the binding of fibrinogen to platelet 
glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. 
The present invention also includes pharmaceutical compositions containing 
such compounds of Formula I, and methods of using such compounds for the 
inhibition of platelet aggregation, as thrombolytics, and/or for the 
treatment of thromboembolic disorders. 
The present invention also includes methods of treating thromboembolic 
disorders by administering a compound of Formula I in combination with one 
or more second therapeutic agents selected from: anti-coagulants such as 
warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or 
ticlopidine; thrombin inhibitors such as boropeptides, hirudin or 
argatroban; or thrombolytic agents such as tissue plasminogen activator, 
anistreplase, urokinase or streptokinase; or combinations thereof. 
Also included in the present invention are pharmaceutical kits comprising 
one or more containers containing pharmaceutical dosage units comprising a 
compound of Formula I, for the treatment of thromboembolic disorders.

DETAILED DESCRIPTION OF THE INVENTION 
This invention provides novel aromatic compounds containing basic and 
acidic termini of Formula I (described below) which are useful as 
antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds 
of the present invention inhibit the binding of fibrinogen to the platelet 
glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. 
The present invention also includes pharmaceutical compositions containing 
such compounds of Formula I, and methods of using such compounds for the 
inhibition of platelet aggregation, as thrombolytics, and/or for the 
treatment of thromboembolic disorders. 
The present invention provides compounds of the Formula I: 
##STR3## 
or pharmaceutically acceptable salt or prodrug forms thereof wherein: 
W is selected from --NR.sup.6 R.sup.6a, --C(.dbd.NR.sup.6)NHR.sup.6a, 
--NR.sup.6 --C(.dbd.NR.sup.6a)NHR.sup.8, piperazinyl, or piperidinyl; 
Y is selected from --C(R.sup.7).sub.2 --, --C(.dbd.O)--, --S(O).sub.p --, 
--O--, --N(R.sup.6)--, --NR.sup.6 C(.dbd.O)--, --C(.dbd.O)N(R.sup.6)-- or 
a single bond; 
with the proviso that when n=0, then the bond between W and Y is not a 
heteroatom to heteroatom bond; 
with the proviso that when n=0 and W is NH.sub.2, then Y is not 
--C(.dbd.O)-- or --C(.dbd.O)N(R.sup.6)--; 
with the proviso that when n=1 and W is --NR.sup.6 R.sup.6a, then Y is not 
--S(O).sub.p --, --O--, --N(R.sup.6)--, or --NR.sup.6 C(.dbd.O)--; 
L.sup.1 and L.sup.2 are independently selected from: 
a single bond, 
--(C.sub.1 to C.sub.4 alkyl)--, substituted with 0-8 R.sup.5b, 
--(C.sub.2 to C.sub.4 alkenyl)--, substituted with 0-6 R.sup.5b, 
--(C.sub.2 to C.sub.4 alkynyl)--, substituted with 0-4 R.sup.5b, 
--(cyclopropyl)--, substituted with 0-1 R.sup.5b, 
with the proviso that at least one of L.sup.1 or L.sup.2, but not both of 
L.sup.1 or L.sup.2, are a bond; 
alternatively, L.sup.1 is taken together with R.sup.2 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1 R.sup.5 ; 
alternatively, L.sup.2 is taken together with R.sup.3 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1 R.sup.5 ; 
Z is selected from --C(.dbd.O)-- or --S(O).sub.p --; 
X is selected from --C(.dbd.O)--, --S(O).sub.p --, O, --N(R.sup.6)--, 
--NR.sup.6 C(.dbd.O)--, --C(.dbd.O)N(R.sup.6)--, or a single bond; 
A is selected from CO.sub.2 R.sup.9, SO.sub.3 H, tetrazolyl, or PO.sub.3 H; 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.7 are independently selected 
from: 
H, 
C.sub.1 to C.sub.8 alkyl substituted with 0-5 R.sup.5, 
C.sub.2 to C.sub.8 alkenyl substituted with 0-5 R.sup.5 
C.sub.3 to C.sub.8 alkynyl substituted with 0-5 R.sup.5, 
C.sub.3 to C.sub.8 cycloalkyl substituted with 0-5 R.sup.5, 
C.sub.4 to C.sub.8 cycloalkylalkyl substituted with 0-5 R.sup.5, 
C.sub.7 to C.sub.11 arylalkyl substituted with 0-5 R.sup.5, 
C.sub.1 to C.sub.4 alkoxy substituted with 0-5 R.sup.5, 
aryl substituted with 0-5 R.sup.5 ; 
a 5-10-membered heterocyclic ring system containing 1-4 heteroatoms 
independently selected from N, S, and O, said heterocyclic ring being 
substituted with 0-4 R.sup.5 ; 
F, Cl, Br, I, CF.sub.3, CN, CHO, CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, 
CONHR.sup.5a, CON(R.sup.5a).sub.2, OC(.dbd.O)R.sup.5a, 
OC(.dbd.O)OR.sup.5a, OR.sup.5a, OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 
CO.sub.2 R.sup.5a, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, 
NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, 
NR.sup.5a C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 
N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or 
SO.sub.2 N(R.sup.5a).sub.2 ; 
alternatively, when m or n are 2-6, R.sup.7 can be taken together with 
R.sup.7 bonded to an adjacent carbon atom to form a direct bond, thereby 
to form a double or triple bond between the adjacent carbon atoms; 
R.sup.5 is selected independently from H, F, Cl, Br, I, CF.sub.3, CN, CHO, 
CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, 
OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, 
OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 
CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, NO.sub.2, NR.sup.5a 
C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, NR.sup.5a 
C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 N(R.sup.5a).sub.2, 
NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or SO.sub.2 
N(R.sup.5a).sub.2, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, 
C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
R.sup.5b is selected independently from H, F, Cl, Br, I, CF.sub.3, CN, CHO, 
CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, 
OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, 
OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 
CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, NO.sub.2, NR.sup.5a 
C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, NR.sup.5a 
C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 N(R.sup.5a).sub.2, 
NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or SO.sub.2 
N(R.sup.5a).sub.2, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, 
C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
alternatively, two R.sup.5b groups when attached to adjacent carbon atoms 
may be taken together to form --CH.sub.2 --, thereby to form a 
cyclopropylene group; 
R.sup.5a is selected from: H, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 
alkenyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 
cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 
arylalkyl; 
R.sup.6, R.sup.6a, and R.sup.8 are independently selected from: H, C.sub.1 
to C.sub.4 alkyl, C.sub.3 to C.sub.11 cycloalkyl, C.sub.6 to C.sub.10 
aryl, C.sub.7 to C.sub.11 arylalkyl, C.sub.2 to C.sub.7 alkylcarbonyl, 
C.sub.7 to C.sub.11 arylcarbonyl, C.sub.2 to C.sub.10 alkoxycarbonyl, 
C.sub.4 to C.sub.11 cycloalkoxycarbonyl, C.sub.7 to C.sub.11 
bicycloalkoxycarbonyl, or C.sub.7 to C.sub.11 aryloxycarbonyl; 
R.sup.9 is selected from H, C.sub.1 to C.sub.8 alkyl, C.sub.3 to C.sub.11 
cycloalkyl, C.sub.6 to C.sub.10 aryl, C.sub.7 to C.sub.11 aralkyl, C.sub.3 
to C.sub.10 alkylcarbonyloxyalkyl, C.sub.3 to C.sub.10 
alkoxycarbonyloxyalkyl, C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.5 to 
C.sub.10 cycloalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
cycloalkoxycarbonyloxyalkyl, C.sub.5 to C.sub.10 cycloalkoxycarbonyl, 
C.sub.7 to C.sub.11 aryloxycarbonyl, C.sub.8 to C.sub.12 
aryloxycarbonyloxyalkyl, C.sub.8 to C.sub.12 arylcarbonyloxyalkyl, C.sub.5 
to C.sub.10 alkoxyalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
(5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyl, or C.sub.10 to C.sub.14 
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl; 
m is an integer from 1-6, with the proviso that m plus n cannot be greater 
than 6; 
n is an integer from an integer from 0 to 6; 
p is an integer from 0 to 2. 
The present invention also provides compounds of the Formula Ia: 
##STR4## 
or pharmaceutically acceptable salt or prodrug forms thereof wherein: 
W is selected from --NR.sup.6 R.sup.6a, --C (.dbd.NR.sup.6)NHR.sup.6a, 
--NR.sup.6 --C(.dbd.NR.sup.6a)NHR.sup.8, piperazinyl, or piperidinyl; 
Y is selected from --CH.sub.2 --, --C(.dbd.O)--, --S(O).sub.p --, --O--, 
--N(R.sup.6)--, --NR.sup.6 C(.dbd.O)--, --C(.dbd.O)N(R.sup.6)-- or a 
single bond; 
with the proviso that when n=0, then the bond between W and Y is not a 
heteroatom to heteroatom bond; 
with the proviso that when n=0 and W is NH.sub.2, then Y is not 
--C(.dbd.O)-- or --C(.dbd.O)N(R.sup.6)--; 
with the proviso that when n=1 and W is --NR.sup.6 R.sup.6a, then Y is not 
--S(O).sub.p --, --O--, --N(R.sup.6)--, or --NR.sup.6 C(.dbd.O)--; 
L.sup.1 and L.sup.2 are independently selected from: 
a single bond, 
--(C.sub.1 to C.sub.4 alkyl)-- substituted with 0-4 R.sup.5b, 
--(C.sub.2 to C.sub.4 alkenyl)-- substituted with 0-4 R.sup.5b, 
--(C.sub.2 to C.sub.4 alkynyl)-- substituted with 0-3 R.sup.5b, 
--(cyclopropyl)--, substituted with 0-1 R.sup.5b, 
with the proviso that at least one of L.sup.1 or L.sup.2, but not both of 
L.sup.1 or L.sup.2 are a bond; 
alternatively, L.sup.1 is taken together with R.sup.2 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1 R.sup.5 ; 
alternatively, L.sup.2 is taken together with R.sup.3 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1 R.sup.5 ; 
Z is selected from --C(.dbd.O)-- or --S(O).sub.p --; 
X is selected from --C(.dbd.O)--, --S(O).sub.p --, O, --N(R.sup.6)--, 
--NR.sup.6 C(.dbd.O)--, --C(.dbd.O)N(R.sup.6)--, or a single bond; 
A is selected from CO.sub.2 R.sup.9, SO.sub.3 H, tetrazolyl, or PO.sub.3 H; 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.7 are independently selected 
from: 
H, 
C.sub.1 to C.sub.8 alkyl substituted with 0-4 R.sup.5, 
C.sub.2 to C.sub.8 alkenyl substituted with 0-4 R.sup.5 
C.sub.3 to C.sub.8 alkynyl substituted with 0-4 R.sup.5, 
C.sub.3 to C.sub.8 cycloalkyl substituted with 0-4 R.sup.5, 
C.sub.4 to C.sub.8 cycloalkylalkyl substituted with 0-4 R.sup.5, 
C.sub.6 to C.sub.10 aryl substituted with 0-2 R.sup.5, 
C.sub.7 to C.sub.11 arylalkyl substituted with 0-2 R.sup.5, 
C.sub.1 to C.sub.4 haloalkoxy, 
F, Cl, Br, I, CF.sub.3, CN, CHO, CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, 
CONHR.sup.5a, CON(R.sup.5a).sub.2, OC(.dbd.O)R.sup.5a, 
OC(.dbd.O)OR.sup.5a, OR.sup.5a, OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 
CO.sub.2 R.sup.5a, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, 
NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, 
NR.sup.5a C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 
N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or 
SO.sub.2 N(R.sup.5a).sub.2 ; 
R.sup.5 is selected independently from H, F, Cl, Br, I, CF.sub.3, CN, CHO, 
CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, 
OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, 
OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 
CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, NO.sub.2, NR.sup.5a 
C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, NR.sup.5a 
C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 N(R.sup.5a).sub.2, 
NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or SO.sub.2 
N(R.sup.5a).sub.2, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.3 to C.sub.8 cycloalkyl, C.sub.4 to C.sub.8 cycloalkylmethyl, 
C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
R.sup.5b is selected independently from H, F, Cl, Br, I, CF.sub.3, CN, CHO, 
CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, 
OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, 
OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 
CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, NO.sub.2, NR.sup.5a C 
(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, NR.sup.5a 
C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 N (R.sup.5a).sub.2, 
NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or SO.sub.2 
N(R.sup.5a).sub.2, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, 
C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
alternatively, two R.sup.5b groups when attached to adjacent carbon atoms 
may be taken together to form --CH.sub.2 --, thereby to form a 
cyclopropylene group; 
R.sup.5a is selected from: H, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 
alkenyl, C.sub.3 to C.sub.8 cycloalkyl, C.sub.4 to C.sub.8 
cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 
arylalkyl; 
R.sup.6, R.sup.6a, and R.sup.8 are independently selected from: H, C.sub.1 
to C.sub.4 alkyl, C.sub.3 to C.sub.10 cycloalkyl, C.sub.6 to C.sub.10 
bicycloalkyl, C.sub.6 to C.sub.10 aryl, C.sub.7 to C.sub.11 arylalkyl, 
C.sub.2 to C.sub.7 alkylcarbonyl, C.sub.7 to C.sub.11 arylcarbonyl, 
C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.4 to C.sub.11 
cycloalkoxycarbonyl, C.sub.7 to C.sub.11 bicycloalkoxycarbonyl, or C.sub.7 
to C.sub.11 aryloxycarbonyl; 
R.sup.9 is selected from H, C.sub.1 to C.sub.8 alkyl, C.sub.3 to C.sub.10 
cycloalkyl, C.sub.6 to C.sub.10 aryl, C.sub.7 to C.sub.11 aralkyl, C.sub.3 
to C.sub.10 alkylcarbonyloxyalkyl, C.sub.3 to C.sub.10 
alkoxycarbonyloxyalkyl, C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.5 to 
C.sub.10 cycloalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
cycloalkoxycarbonyloxyalkyl, C.sub.5 to C.sub.10 cycloalkoxycarbonyl, 
C.sub.7 to C.sub.11 aryloxycarbonyl, C.sub.8 to C.sub.12 
aryloxycarbonyloxyalkyl, C.sub.8 to C.sub.12 arylcarbonyloxyalkyl, C.sub.5 
to C.sub.10 alkoxyalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
(5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyl, or C.sub.10 to C.sub.14 
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl; 
m is an integer from 1-6, with the proviso that m plus n cannot be greater 
than 6; 
n is an integer from an integer from 0 to 6; 
p is an integer from 0 to 2. 
Preferred are the above compounds of Formula I wherein L.sup.1 is a bond. 
Preferred compounds of the present invention are compounds of the Formula 
Ib: 
##STR5## 
or pharmaceutically acceptable salt or prodrug forms thereof wherein: W is 
selected from --NR.sup.6 R.sup.6a, --C(.dbd.NR.sup.6)NHR.sup.6a, 
--NR.sup.6 --C(.dbd.NR.sup.6a)NHR.sup.8, piperazinyl, or piperidinyl; 
Y is selected from --CH.sub.2 --, --C(.dbd.O)--, --S(O).sub.p --, --O--, 
--N(R.sup.6)--, --NR.sup.6 C(.dbd.O)--, --C(.dbd.O)N(R.sup.6)-- or a 
single bond; 
with the proviso that when n=0, then the bond between W and Y is not a 
heteroatom to heteroatom bond; 
with the proviso that when n=0 and W is NH.sub.2, then Y is not 
--C(.dbd.O)-- or --C(.dbd.O)N(R.sup.6)--; 
with the proviso that when n=1 and W is --NR.sup.6 R.sup.6a, then Y is not 
--S(O).sub.p --, --O--, --N(R.sup.6)--, or --NR.sup.6 C(.dbd.O)--; 
L.sup.1 and L.sup.2 are independently selected from: 
a single bond, 
--(C.sub.1 to C.sub.4 alkyl)-- substituted with 0-4 R.sup.5b, 
--(C.sub.2 to C.sub.4 alkenyl)-- substituted with 0-4 R.sup.5b, 
--(C.sub.2 to C.sub.4 alkynyl)-- substituted with 0-3 R.sup.5b, 
--(cyclopropyl)--, substituted with 0-1 R.sup.5b, 
with the proviso that at least one of L.sup.1 or L.sup.2, but not both of 
L.sup.1 or L.sup.2, are a bond; 
alternatively, L.sup.1 is taken together with R.sup.2 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1 R.sup.5 ; 
alternatively, L.sup.2 is taken together with R.sup.3 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1 R.sup.5 ; 
Z is selected from --C(.dbd.O)-- or --S(O).sub.p --; 
X is selected from --C(.dbd.O)--, --S(O).sub.p --, O, --N(R.sup.6)--, 
--NR.sup.6 C (.dbd.O)--, --C(.dbd.O)N(R.sup.6)--, or a single bond; 
A is selected from CO.sub.2 R.sup.9, SO.sub.3 H, tetrazolyl, or PO.sub.3 H; 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.7 are independently selected 
from: 
H, 
C.sub.1 to C.sub.8 alkyl substituted with 0-4 R.sup.5, 
C.sub.2 to C.sub.8 alkenyl substituted with 0-4 R.sup.5 
C.sub.3 to C.sub.8 alkynyl substituted with 0-4 R.sup.5, 
C.sub.3 to C.sub.8 cycloalkyl substituted with 0-4 R.sup.5, 
C.sub.4 to C.sub.8 cycloalkylalkyl substituted with 0-4 R.sup.5, 
C.sub.6 to C.sub.10 aryl substituted with 0-2 R.sup.5, 
C.sub.7 to C.sub.11 arylalkyl substituted with 0-2 R.sup.5, 
C.sub.1 to C.sub.4 haloalkoxy, 
F, Cl, Br, I, CF.sub.3, CN, CHO, CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, 
CONHR.sup.5a, CON(R.sup.5a).sub.2, OC(.dbd.O)R.sup.5a, 
OC(.dbd.O)OR.sup.5a, OR.sup.5a, OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 
CO.sub.2 R.sup.5a, CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, 
NO.sub.2, NR.sup.5a C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, 
NR.sup.5a C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 
N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or 
SO.sub.2 N(R.sup.5a).sub.2 ; 
R.sup.5 is selected independently from H, F, Cl, Br, I, CF.sub.3, CN, CHO, 
CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, 
OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, 
OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 
CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, NO.sub.2, NR.sup.5a 
C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, NR.sup.5a 
C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 N(R.sup.5a).sub.2, 
NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a or SO.sub.2 
N(R.sup.5a).sub.2, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.3 to C.sub.8 cycloalkyl, C.sub.4 to C.sub.8 cycloalkylmethyl, 
C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
R.sup.5b is selected independently from H, F, Cl, Br, I, CF.sub.3, CN, CHO, 
CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, 
OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, 
OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 
CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, NO.sub.2, NR.sup.5a 
C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, NR.sup.5a 
C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 N(R.sup.5a).sub.2, 
NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, or SO.sub.2 
N(R.sup.5a).sub.2, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.3 to C.sub.11 cycloalkyl, C.sub.4 to C.sub.11 cycloalkylmethyl, 
C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
alternatively, two R.sup.5b groups when attached to adjacent carbon atoms 
may be taken together to form --CH.sub.2 --, thereby to form a 
cyclopropylene group; 
R.sup.5a is selected from: H, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 
alkenyl, C.sub.3 to C.sub.8 cycloalkyl, C.sub.4 to C.sub.8 
cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 
arylalkyl; 
R.sup.6, R.sup.6a, and R.sup.8 are independently selected from: H, C.sub.1 
to C.sub.4 alkyl, C.sub.3 to C.sub.10 cycloalkyl, C.sub.6 to C.sub.10 
bicycloalkyl, C.sub.6 to C.sub.10 aryl, C.sub.7 to C.sub.11 arylalkyl, 
C.sub.2 to C.sub.7 alkylcarbonyl, C.sub.7 to C.sub.11 arylcarbonyl, 
C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.4 to C.sub.11 
cycloalkoxycarbonyl, C.sub.7 to C.sub.11 bicycloalkoxycarbonyl, or C.sub.7 
to C.sub.11 aryloxycarbonyl; 
R.sup.9 is selected from H, C.sub.1 to C.sub.8 alkyl, C.sub.3 to C.sub.10 
cycloalkyl, C.sub.6 to C.sub.10 aryl, C.sub.7 to C.sub.11 aralkyl, C.sub.3 
to C.sub.10 alkylcarbonyloxyalkyl, C.sub.3 to C.sub.10 
alkoxycarbonyloxyalkyl, C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.5 to 
C.sub.10 cycloalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
cycloalkoxycarbonyloxyalkyl, C.sub.5 to C.sub.10 cycloalkoxycarbonyl, 
C.sub.7 to C.sub.11 aryloxycarbonyl, C.sub.8 to C.sub.12 
aryloxycarbonyloxyalkyl, C.sub.8 to C.sub.12 arylcarbonyloxyalkyl, C.sub.5 
to C.sub.10 alkoxyalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
(5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyl, or C.sub.10 to C.sub.14 
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl; 
m is an integer from 1-6, with the proviso that m plus n cannot be greater 
than 6; 
n is an integer from an integer from 0 to 6; 
p is an integer from 0 to 2. 
Preferred compounds of the present invention are compounds of Formula I, 
Ia, or Ib wherein: 
W is selected from --NR.sup.6 R.sup.6a, --C(.dbd.NR.sup.6)NHR.sup.6a, 
--NR.sup.6 --C(.dbd.NR.sup.6a)NHR.sup.8, piperazinyl; 
Y is selected from O, CH.sub.2, S or a single bond; 
L.sup.1 and L.sup.2 are independently selected from: 
a single bond, 
--CH.sub.2 CH.sub.2 -- substituted with 0-2 R.sup.5b, or 
--CH.dbd.CH-- substituted with 0-2 R.sup.5 b; 
--(cyclopropyl)-- substituted with 0-1 R.sup.5 b; 
with the proviso that at least one of L.sup.1 or L.sup.2, but not both of 
L.sup.1 or L.sup.2, are a bond; 
alternatively, L.sup.1 is taken together with R.sup.2 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1R.sup.5 ; 
alternatively, L.sup.2 is taken together with R.sup.3 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1R.sup.5 ; 
Z is selected from --C(.dbd.O)-- or --S(O).sub.p --; 
X is selected from --O-- or a single bond; 
A is selected from CO.sub.2 R.sup.9, SO.sub.3 H tetrazolyl, or PO.sub.3 H; 
R.sup.1 and R.sup.2 are independently selected from: 
H, 
C.sub.1 to C.sub.8 alkyl substituted with 0-2 R.sup.5, 
C.sub.2 to C.sub.8 alkenyl substituted with 0-2 R.sup.5, 
C.sub.3 to C.sub.8 cycloalkyl substituted with 0-2 R.sup.5, 
C.sub.4 to C.sub.8 cycloalkylmethyl substituted with 0-2 R.sup.5, 
OR.sup.5a ; 
R.sup.3, R.sup.4, and R.sup.7 are independently selected from: 
H, 
C.sub.1 to C.sub.8 alkyl substituted with 0-2 R.sup.5, 
C.sub.2 to C.sub.8 alkenyl substituted with 0-2 R.sup.5, 
C.sub.3 to C.sub.8 cycloalkyl substituted with 0-2 R.sup.5, 
C.sub.4 to C.sub.8 cycloalkylmethyl substituted with 0-2 R.sup.5, 
C.sub.7 to C.sub.11 arylalkyl substituted with 0-2 R.sup.5, 
aryl substituted with 0-2 R.sup.5, 
F, Cl, Br, I CO.sub.2 R.sup.5a, OR.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5a, 
CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5a, or NO.sub.2 ; 
R.sup.5 is selected independently from H, F, Cl, Br, I, CF.sub.3, CN, CHO, 
CO.sub.2 R.sup.5a, C(.dbd.O)R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, 
OC(.dbd.O)R.sup.5a, OC(.dbd.O)OR.sup.5a, OR.sup.5a, 
OC(.dbd.O)N(R.sup.5a).sub.2, OCH.sub.2 CO.sub.2 R.sup.5a, CO.sub.2 
CH.sub.2 CO.sub.2 R.sup.5a, N(R.sup.5a).sub.2, NO.sub.2, NR.sup.5a 
C(.dbd.O)R.sup.5a, NR.sup.5a C(.dbd.O)OR.sup.5a, NR.sup.5a 
C(.dbd.O)N(R.sup.5a).sub.2, NR.sup.5a SO.sub.2 N(R.sup.5a).sub.2, 
NR.sup.5a SO.sub.2 R.sup.5a, S(O).sub.p R.sup.5a, SO.sub.2 N 
(R.sup.5a).sub.2, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.3 to C.sub.8 cycloalkyl, C.sub.4 to C.sub.8 cycloalkylmethyl, 
C.sub.6 to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
R.sup.5b is selected independently from H, CF.sub.3, CN, CHO, CO.sub.2 
R.sup.5a, CONHR.sup.5a, CON(R.sup.5a).sub.2, OR.sup.5a, N(R.sup.5a).sub.2, 
C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.3 to C.sub.11 
cycloalkyl, C.sub.4 to C.sub.7 cycloalkylmethyl, C.sub.6 to C.sub.10 aryl, 
or C.sub.7 to C.sub.11 arylalkyl; 
alternatively, two R.sup.5b groups when attached to adjacent carbon atoms 
may be taken together to form --CH.sub.2 --, thereby to form a 
cyclopropylene group; 
R.sup.5a are selected independently from: H, C.sub.1 to C.sub.6 alkyl, 
C.sub.2 to C.sub.6 alkenyl, C.sub.4 to C.sub.8 cycloalkylmethyl, C.sub.6 
to C.sub.10 aryl, or C.sub.7 to C.sub.11 arylalkyl; 
R.sup.6, R.sup.6a, and R.sup.8 are independently selected from H, C.sub.1 
to C.sub.4 alkyl, C.sub.2 to C.sub.7 alkylcarbonyl, C.sub.7 to C.sub.11 
arylcarbonyl, C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.4 to C.sub.11 
cycloalkoxycarbonyl, C.sub.7 to C.sub.11 bicycloalkoxycarbonyl, or C.sub.7 
to C.sub.11 aryloxycarbonyl; 
R.sup.9 is selected from H, C.sub.1 to C.sub.4 alkyl, C.sub.3 to C.sub.10 
alkylcarbonyloxyalkyl, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyl, 
C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.5 to C.sub.10 
cycloalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
cycloalkoxycarbonyloxyalkyl, C.sub.5 to C.sub.10 cycloalkoxycarbonyl, 
C.sub.7 to C.sub.11 aryloxycarbonyl, C.sub.8 to C.sub.12 
aryloxycarbonyloxyalkyl, C.sub.8 to C.sub.12 arylcarbonyloxyalkyl, C.sub.5 
to C.sub.10 alkoxyalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
(5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyl, or C.sub.10 to C.sub.14 
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl; 
m is an integer from 1 or 2; 
n is an integer from 1 to 3; 
p is an integer from 0 to 2; 
or pharmaceutically acceptable salt or prodrug forms thereof. 
More preferred compounds are those compounds of Formula I wherein: 
W is selected from --NR.sup.6 R.sup.6a, --NR.sup.6 
--C(.dbd.NR.sup.6a)NHR.sup.8, piperazinyl; 
Y is selected from O, S, or a single bond; 
L.sup.1 and L.sup.2 are selected from: 
a bond; 
--CH.dbd.CH-- substituted with 0-2 R.sup.5b ; or 
--(cyclopropyl)-- substituted with 0-1 R.sup.5b ; 
with the proviso that at least one of L.sup.1 or L.sup.2, but not both of 
L.sup.1 or L.sup.2, are a bond; 
alternatively, L.sup.2 is taken together with R.sup.3 to form a benzo-fused 
ring, said benzo-fused ring being substituted with 0-1R.sup.5 ; 
Z is selected from--C(.dbd.O)-- or S(O).sub.p ; 
X is selected from O or a single bond; 
A is selected from CO.sub.2 R.sup.9 ; 
R.sup.1 and R.sup.2 are independently selected from: 
H, 
C.sub.1 to C.sub.8 alkyl substituted with 0-2 R.sup.5, 
C.sub.2 to C.sub.8 alkenyl substituted with 0-2 R.sup.5, 
C.sub.4 to C.sub.8 cycloalkylmethyl, 
OR.sup.5a ; 
R.sup.3 and R.sup.4 are independently selected from: 
H, 
C.sub.1 to C.sub.6 alkyl substituted with 0-2 R.sup.5, 
I, F, Br, Cl, CO.sub.2 R.sup.5a, OR.sup.5a, OCH.sub.2 CO.sub.2 R.sup.5a, 
CO.sub.2 CH.sub.2 CO.sub.2 R.sup.5a, or NO.sub.2 ; 
R.sup.5, R.sup.7, R.sup.5a, and R.sup.5b are independently selected from H, 
C.sub.1 to C.sub.6 straight or branched alkyl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.4 to C.sub.7 cycloalkylmethyl, or C.sub.7 to C.sub.11 arylalkyl; 
R.sup.6, R.sup.6a, and R.sup.8 are independently selected from H, C.sub.1 
to C.sub.2 alkyl, C.sub.2 to C.sub.7 alkylcarbonyl, C.sub.7 to C.sub.11 
arylcarbonyl, C.sub.2 to C.sub.10 alkoxycarbonyl, C.sub.4 to C.sub.11 
cycloalkoxycarbonyl, C.sub.7 to C.sub.11 bicycloalkoxycarbonyl, or C.sub.7 
to C.sub.11 aryloxycarbonyl; 
R.sup.9 is selected from H, C.sub.1 to C.sub.4 alkyl, C.sub.3 to C.sub.10 
alkylcarbonyloxyalkyl, C.sub.3 to C.sub.10 alkoxycarbonyloxyalkyl, C.sub.2 
to C.sub.10 alkoxycarbonyl, C.sub.5 to C.sub.10 
cycloalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
cycloalkoxycarbonyloxyalkyl, C.sub.5 to C.sub.10 cycloalkoxycarbonyl, 
C.sub.7 to C.sub.11 aryloxycarbonyl, C.sub.8 to C.sub.12 
aryloxycarbonyloxyalkyl, C.sub.8 to C.sub.12 arylcarbonyloxyalkyl, C.sub.5 
to C.sub.10 alkoxyalkylcarbonyloxyalkyl, C.sub.5 to C.sub.10 
(5-alkyl-1,3-dioxa-cyclopenten-2-one-yl) methyl, or C.sub.10 to C.sub.14 
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl; 
m is selected from 1 or 2; 
n is an integer from 1 to 3; 
p is selected from 0, 1,or 2; 
and pharmaceutically acceptable salts thereof. 
Further preferred are those compounds described above, or a 
pharmaceutically acceptable salt form thereof, wherein L.sup.1 is a bond 
and L.sup.2 is --CH.sub.2 .dbd.CH.sub.2 --. 
Specifically preferred compounds of the present invention are compounds, or 
a pharmaceutically acceptable salt or prodrug form thereof, selected from: 
(a) (E)-ethyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate; 
(b) (E)-(carboxymethyl) 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate; 
(c) (E)-ethyl 
5-[3-((3-(2-aminoethoxy)-5-ethoxyphenyl))-3-oxo-1-propenyl]-2-(carboxymeth 
oxy)benzoate; 
(d) (E)-4-[3-((3-(2-aminoethoxy)-5-ethoxyphenyl)) 
-3-oxo-1-propenyl]phenoxyacetic acid; 
(e) (E)-ethyl 
5-[3-((3-(2-aminopropyl)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate; 
(f) (E)-benzyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate; 
(g) (E)-methyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate; 
(h) 
(E)-4-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-nitrophenoxyaceti 
c acid; 
(i) (E)-ethyl 5-[3-((2-(1-prop-2-enyloxy)-5-(2-aminoethoxy) 
phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzoate; 
(j) (E)-n-butyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate; 
(k) 
(E)-4-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-ethoxyphenoxyacet 
ic acid; 
(l) (E)-(carboxymethyl) 
5-[3-((2-(benzyloxy)-5-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carbox 
ymethoxy)benzoate; 
(m) (E)-(carboxymethyl) 
5-((3-((2-(1-prop-2-enyloxy)-5-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl))- 
2-(carboxymethoxy)benzoate; 
(n) 
(E)-4-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-3-methoxyphenoxyace 
tic acid; 
(o) (E)-(2-ethoxy-2-oxoethyl) 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate; 
(p) 
(E)-4-[3-((3-(aminomethyl)phenyl))-3-oxo-1-propenyl]benzene-1,2-bis(oxyace 
tic acid); 
(q) 
(E)-4-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]benzene-1,2-bis(oxya 
cetic acid); 
(r) (E)-4-[3-((3-(2-aminoethoxy) 
phenyl))-3-oxo-1-propenyl]-2-methoxyphenoxyacetic acid; 
(s) (E)-4-[3-((3-(2-aminoethyl) 
phenyl))-3-oxo-1-propenyl]-2-ethoxyphenoxyacetic acid; 
(t) (E)-4-[3-((3-(2-aminoethoxy) phenyl))-3-oxo-1-propenyl]phenoxyacetic 
acid; 
(u) 
(E)-4-[3-((3-(1-piperazinyl)phenyl)-3-oxo-1-propenyl]-2-methoxyphenoxyacet 
ic acid; 
(v) 
(E)-4-[3-((3-(guanidinylmethyl)phenyl))-3-oxo-1-propenyl]-2-methoxyphenoxy 
acetic acid; 
(w) 
(E)-4-[3-((3-(2-(methylamino)ethoxy)phenyl))-3-oxo-1-propenyl]-2-methoxyph 
enoxyacetic acid; 
(x) (E)-4-[3-((3-(1-piperazinyl)phenyl))-3-oxo- 
1-propenyl]-2-nitrophenoxyacetic acid; 
(y) (E)-ethyl 
5-[3-((2-(3-methyl-1-butoxy)-5-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2 
-(carboxymethoxy)benzoate; 
(z) (E)-Methyl 5-[[3-[3-((2-(methylamino) 
ethoxy))-phenyl]-3-oxo-1-propenyl]]-2-(carboxymethoxy)-benzoate; 
(aa) 
(E)-4-[3-((5-(2-aminoethoxy)-2-benzyloxy-phenyl))-1-oxo-1-prop-2-enyl]-2-e 
thoxyphenoxy-acetic acid; 
(bb) 
(E)-4-[2-((3-(2-aminoethoxy)phenylsulfonyl))-ethenyl]-2-nitrophenoxyacetic 
acid; 
(cc) (E)-4-[2-((3-(2-aminoethoxy)phenylthio))-ethenyl]-2-nitrophenoxyacetic 
acid; 
(dd) 
(E)-4-[2-((3-(2-aminoethoxy)phenylsulfoxo))-ethenyl]-2-nitrophenoxyacetic 
acid; 
(ee) 
(E)-4-[[1-[2-((3-(2-aminoethoxy)phenyl))-ethenyl]sulfonyl-2-methoxyphenoxy 
acetic acid; 
(ff) 
(E)-4-[[1-[2-((3-(2-aminoethoxy)phenyl))-ethenyl]sulfoxo-2-methoxyphenoxya 
cetic acid; 
(gg) 
(E)-4-[[1-[2-((3-(2-aminoethoxy)phenyl))-ethenyl]thio-2-methoxyphenoxyacet 
ic acid. 
In the present invention it has been discovered that the compounds of 
Formula I above are useful as inhibitors of glycoprotein IIb/IIIa 
(GPIIb/IIIa). The compounds of the present invention inhibit the 
activation and aggregation of platelets induced by all known endogenous 
platelet agonists. 
The present invention also provides pharmaceutical compositions comprising 
a compound of Formula I and a pharmaceutically acceptable carrier. 
The compounds of Formula I of the present invention are useful for the 
treatment (including prevention) of thromboembolic disorders. The term 
thromboembolic disorders as used herein includes conditions involving 
platelet activation and aggregation, such as arterial or venous 
cardiovascular or cerebrovascular thromboembolic disorders, including, for 
example, unstable angina, first or recurrent myocardial infarction, 
ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, 
venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial 
embolism, coronary and cerebral arterial thrombosis, myocardial 
infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or 
diabetes, comprising administering to a mammal in need of such treatment a 
therapeutically effective amount of a compound of Formula I described 
above. 
The compounds of the present invention are useful for inhibiting the 
binding of fibrinogen to blood platelets, inhibiting aggregation of blood 
platelets, treating thrombus formation or embolus formation, or preventing 
thrombus or embolus formation in a mammal. The compounds of the invention 
may be used as a medicament for blocking fibrinogen from acting at its 
receptor site in a mammal. 
Compounds of the invention may be administered to patients where prevention 
of thrombosis by inhibiting binding of fibrinogen to the platelet membrane 
glycoprotein complex IIb/IIIa receptor is desired. They are useful in 
surgery on peripheral arteries (arterial grafts, carotid endarterectomy) 
and in cardiovascular surgery where manipulation of arteries and organs, 
and/or the interaction of platelets with artificial surfaces, leads to 
platelet aggregation and consumption, and where the aggregated platelets 
may form thrombi and thromboemboli. The compounds of the present invention 
may be administered to these surgical patients to prevent the formation of 
thrombi and thromboemboli. 
Extracorporeal circulation is routinely used for cardiovascular surgery in 
order to oxygenate blood. Platelets adhere to surfaces of the 
extracorporeal circuit. Adhesion is dependent on the interaction between 
GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the 
surface of the circuit. Platelets released from artificial surfaces show 
impaired homeostatic function. Compounds of the invention may be 
administered to prevent adhesion. 
Other applications of these compounds include prevention of platelet 
thrombosis, thromboembolism, and reocclusion during and after thrombolytic 
therapy and prevention of platelet thrombosis, thromboembolism and 
reocclusion after angioplasty of coronary and other arteries and after 
coronary artery bypass procedures. The compounds of the present invention 
may also be used to prevent myocardial infarction. The compounds of the 
present invention are useful as thrombolytics for the treatment of 
thromboembolic disorders. 
The compounds of the present invention can also be administered in 
combination with one or more additional therapeutic agents select from: 
anti-coagulant or coagulation inhibitory agents, such as heparin or 
warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, 
piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, 
hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as 
plasminogen activators, anistreplase, urokinase, or streptokinase. 
The compounds of Formula I of the present invention can be administered in 
combination with one or more of the foregoing additional therapeutic 
agents, thereby to reduce the doses of each drug required to achieve the 
desired therapeutic effect. Thus, the combination treatment of the present 
invention permits the use of lower doses of each component, with reduced 
adverse, toxic effects of each component. A lower dosage minimizes the 
potential of side effects of the compounds, thereby providing an increased 
margin of safety relative to the margin of safety for each component when 
used as a single agent. Such combination therapies may be employed to 
achieve synergistic or additive therapeutic effects for the treatment of 
thromboembolic disorders. 
By "therapeutically effective amount" it is meant an amount of a compound 
of Formula I that when administered alone or in combination with an 
additional therapeutic agent to a cell or mammal is effective to prevent 
or ameliorate the thromboembolic disease condition or the progression of 
the disease. 
By "administered in combination" or "combination therapy" it is meant that 
the compound of Formula I and one or more additional therapeutic agents 
are administered concurrently to the mammal being treated. When 
administered in combination each component may be administered at the same 
time or sequentially in any order at different points in time. Thus, each 
component may be administered separately but sufficiently closely in time 
so as to provide the desired therapeutic effect. 
The term anti-coagulant agents (or coagulation inhibitory agents), as used 
herein, denotes agents that inhibit blood coagulation. Such agents include 
warfarin (available as Coumadin.TM.) and heparin. 
The term anti-platelet agents (or platelet inhibitory agents), as used 
herein, denotes agents that inhibit platelet function such as by 
inhibiting the aggregation, adhesion or granular secretion of platelets. 
Such agents include the various known non-steroidal anti-inflammatory 
drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, 
indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and 
piroxicam, including pharmaceutically acceptable salts or prodrugs 
thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and 
piroxicam. Piroxicam is commercially available from Pfizer Inc. (New York, 
N.Y.), as Feldane.TM.. Other suitable anti-platelet agents include 
ticlopidine, including pharmaceutically acceptable salts or prodrugs 
thereof. Ticlopidine is also a preferred compound since it is known to be 
gentle on the gastro-intestinal tract in use. Still other suitable 
platelet inhibitory agents include thromboxane-A2-receptor antagonists and 
thromboxane-A2-synthetase inhibitors, as well as pharmaceutically 
acceptable salts or prodrugs thereof. 
The phrase thrombin inhibitors (or anti-thrombin agents), as used herein, 
denotes inhibitors of the serine protease thrombin. By inhibiting 
thrombin, various thrombin-mediated processes, such as thrombin-mediated 
platelet activation (that is, for example, the aggregation of platelets, 
and/or the granular secretion of plasminogen activator inhibitor-1 and/or 
serotonin) and/or fibrin formation are disrupted. Such inhibitors include 
boropeptides, hirudin and argatroban, including pharmaceutically 
acceptable salts and prodrugs thereof. Preferably the thrombin inhibitors 
are boropeptides. By boropeptides, it is meant, N-acetyl and peptide 
derivatives of boronic acid, such as C-terminal (.alpha.-aminoboronic acid 
derivatives of lysine, ornithine, arginine, homoarginine and corresponding 
isothiouronium analogs thereof. The term hirudin, as used herein, includes 
suitable derivatives or analogs of hirudin, referred to herein as 
hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors 
include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and 
European Patent Application Publication Number 293 881 A2, the disclosures 
of which are hereby incorporated herein by reference. Other suitable 
boropeptide thrombin inhibitors include those disclosed in PCT Application 
Publication Number 92/07869 and European Patent Application Publication 
Number 471 651 A2, the disclosures of which are hereby incorporated herein 
by reference, in their entirety. 
The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or 
fibrinolytics), as used herein, denotes agents that lyse blood clots 
(thrombi). Such agents include tissue plasminogen activator, anistreplase, 
urokinase or streptokinase, including pharmaceutically acceptable salts or 
prodrugs thereof. Tissue plasminogen activator (tPA) is commercially 
available from Genentech Inc., South San Francisco, Calif. The term 
anistreplase, as used herein, refers to anisoylated plasminogen 
streptokinase activator complex, as described, for example, in European 
Patent Application No. 028,489, the disclosures of which are hereby 
incorporated herein by reference herein, in their entirety. Anistreplase 
is commercially available as Eminase.TM.. The term urokinase, as used 
herein, is intended to denote both dual and single chain urokinase, the 
latter also being referred to herein as prourokinase. 
Administration of the compounds of Formula I of the invention in 
combination with such additional therapeutic agent, may afford an efficacy 
advantage over the compounds and agents alone, and may do so while 
permitting the use of lower doses of each. A lower dosage minimizes the 
potential of side effects, thereby providing an increased margin of 
safety. 
GPIIb/IIIa is known to be overexpressed in metastatic tumor cells. The 
compounds or combination products of the present invention may also be 
useful for the treatment, including prevention, of metastatic cancer. 
The compounds herein described may have asymmetric centers. Unless 
otherwise indicated, all chiral, diastereomeric and racemic forms are 
included in the present invention. Many geometric isomers of olefins, 
C.dbd.N double bonds, and the like can also be present in the compounds 
described herein, and all such stable isomers are contemplated in the 
present invention. It will be appreciated that compounds of the present 
invention may contain asymmetrically substituted carbon atoms, and may be 
isolated in optically active or racemic forms. It is well known in the art 
how to prepare optically active forms, such as by resolution of racemic 
forms or by synthesis, from optically active starting materials. All 
chiral, diastereomeric, racemic forms and all geometric isomeric forms of 
a structure are intended, unless the specific stereochemistry or isomer 
form is specifically indicated. 
When any variable (for example but not limited to, R.sup.5, R.sup.5a, and 
R.sup.6, p, etc.) occurs more than one time in any constituent or in any 
formula, its definition on each occurrence is independent of its 
definition at every other occurrence. Thus, for example, if a group is 
shown to be substituted with 0-2 R.sup.5, then said group may optionally 
be substituted with up to two R.sup.5 and R.sup.5 at each occurrence is 
selected independently from the defined list of possible R.sup.5. Also, by 
way of example, for the group --N(R.sup.5a).sub.2, each of the two 
R.sup.5a substituents on N is independently selected from the defined list 
of possible R.sup.5a. Similarly, by way of example, for the group 
--C(R.sup.7).sub.2 --, each of the two R.sup.7 substituents on C is 
independently selected from the defined list of possible R.sup.7. 
When a bond to a substituent is shown to cross the bond connecting two 
atoms in a ring, then such substituent may be bonded to any atom on the 
ring. 
When a substituent is listed without indicating the atom via which such 
substituent is bonded to the rest of the compound of Formula I, then such 
substituent may be bonded via any atom in such substituent. For example, 
when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless 
specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may 
be bonded to the rest of the compound of Formula I via any atom in such 
piperazinyl, piperidinyl, tetrazolyl group. 
Combinations of substituents and/or variables are permissible only if such 
combinations result in stable compounds. By stable compound or stable 
structure it is meant herein 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. 
The term "substituted", as used herein, means that any one or more hydrogen 
on the designated atom is replaced with a selection from the indicated 
group, provided that the designated atom's normal valency is not exceeded, 
and that the substitution results in a stable compound. When a substituent 
is keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced. 
As used herein, "alkyl" is intended to include both branched and 
straight-chain saturated aliphatic hydrocarbon groups having the specified 
number of carbon atoms; "haloalkyl" is intended to include both branched 
and straight-chain saturated aliphatic hydrocarbon groups having the 
specified number of carbon atoms, substituted with 1 or more halogen (for 
example --C.sub.v F.sub.w where v=1 to 3 and w=1 to (2v+1)); "alkoxy" 
represents an alkyl group of indicated number of carbon atoms attached 
through an oxygen bridge; "cycloalkyl" is intended to include saturated 
ring groups, including mono-, bi- or poly-cyclic ring systems, such as 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 
and adamantyl; and "biycloalkyl" is intended to include saturated bicyclic 
ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, 
[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. 
"Alkenyl" is intended to include hydrocarbon chains of either a straight 
or branched configuration and one or more unsaturated carbon-carbon bonds 
which may occur in any stable point along the chain, such as ethenyl, 
propenyl and the like; and "alkynyl" is intended to include hydrocarbon 
chains of either a straight or branched configuration and one or more 
triple carbon--carbon bonds which may occur in any stable point along the 
chain, such as ethynyl, propynyl and the like. 
The terms "--(alkyl)--", "--(alkyenyl)--", "--(phenyl)--", and the like, 
refer to alkyl, alkenyl, and phenyl groups, respectively, which are 
connected by two bonds to the rest of the structure of Formula I. Such 
groups may alternatively and equivalently be denoted as "alkylene", 
"alkenylene", "phenylene", and the like, respectively. 
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and 
iodo; and "counterion" is used to represent a small, negatively charged 
species such as chloride, bromide, hydroxide, acetate, sulfate and the 
like. 
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or 
naphthyl; the term "arylalkyl" represents an aryl group attached through 
an alkyl bridge. 
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean 
any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered 
bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any 
of which may be saturated, partially unsaturated, or aromatic. Examples of 
such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, 
cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or 
tetrahydronaphthyl (tetralin). 
As used herein, the term "heterocycle" or "heteroaryl" or "heterocyclic" is 
intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 
10-membered bicyclic heterocyclic ring which may be saturated, partially 
unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 
4 heteroatoms independently selected from the group consisting of N, O and 
S and wherein the nitrogen and sulfur heteroatoms may optionally be 
oxidized, and the nitrogen may optionally be quaternized, and including 
any bicyclic group in which any of the above-defined heterocyclic rings is 
fused to a benzene ring. The heterocyclic ring may be attached to its 
pendant group at any heteroatom or carbon atom which results in a stable 
structure. The heterocyclic rings described herein may be substituted on 
carbon or on a nitrogen atom if the resulting compound is stable. Examples 
of such heterocycles include, but are not limited to, pyridyl (pyridinyl), 
pyrimidinyl, furanyl (furyl) , thiazolyl, thienyl, pyrrolyl, pyrazolyl, 
imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, 
quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, 
pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, 
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or 
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 
6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, 
chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, 
pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, 
pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 
1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, 
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, 
pteridinyl, 4aH-carbazole, carbazole, .beta.-carbolinyl, phenanthridinyl, 
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, 
phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, 
pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, 
pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, 
quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring 
and spiro compounds containing, for example, the above heterocycles. 
As used herein, "pharmaceutically acceptable salts" refer to derivatives of 
the disclosed compounds wherein the parent compound of Formula I is 
modified by making acid or base salts of the compound of Formula I. 
Examples of pharmaceutically acceptable salts include, but are not limited 
to, mineral or organic acid salts of basic residues such as amines; alkali 
or organic salts of acidic residues such as carboxylic acids; and the 
like. 
"Prodrugs" are considered to be any covalently bonded carriers which 
release the active parent drug according to Formula I in vivo when such 
prodrug is administered to a mammalian subject. Prodrugs of the compounds 
of Formula I are prepared by modifying functional groups present in the 
compounds in such a way that the modifications are cleaved, either in 
routine manipulation or in vivo, to the parent compounds. Prodrugs include 
compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl 
groups are bonded to any group that, when administered to a mammalian 
subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl 
group respectively. Examples of prodrugs include, but are not limited to, 
acetate, formate and benzoate derivatives of alcohol and amine functional 
groups in the compounds of Formula I, and the like. Examples of 
representative carboxyl and amino prodrugs are included under the 
definition of R.sup.9, R.sup.6, R.sup.6a, and R.sup.8. 
The pharmaceutically acceptable salts of the compounds of Formula I include 
the conventional non-toxic salts or the quaternary ammonium salts of the 
compounds of Formula I formed, for example, from non-toxic inorganic or 
organic acids. For example, such conventional non-toxic salts include 
those derived from inorganic acids such as hydrochloric, hydrobromic, 
sulfuric, sulfamic, phosphoric, nitric and the like; and the salts 
prepared from organic acids such as acetic, propionic, succinic, glycolic, 
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, 
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane 
disulfonic, oxalic, isethionic, and the like. 
The pharmaceutically acceptable salts of the present invention can be 
synthesized from the compounds of Formula I which contain a basic or 
acidic moiety by conventional chemical methods. Generally, the salts are 
prepared by reacting the free base or acid with stoichiometric amounts or 
with an excess of the desired salt-forming inorganic or organic acid or 
base in a suitable solvent or various combinations of solvents. 
The pharmaceutically acceptable salts of the acids of Formula I with an 
appropriate amount of a base, such as an alkali or alkaline earth metal 
hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an 
organic base such as an amine, e.g., dibenzylethylenediamine, 
trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a 
quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and 
the like. 
As discussed above, pharmaceutically acceptable salts of the compounds of 
the invention can be prepared by reacting the free acid or base forms of 
these compounds with a stoichiometric amount of the appropriate base or 
acid, respectively, in water or in an organic solvent, or in a mixture of 
the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, 
isopropanol, or acetonitrile are preferred. Lists of suitable salts are 
found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing 
Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby 
incorporated by reference. 
The disclosures of all of the references cited herein are hereby 
incorporated herein by reference in their entirety. 
Synthesis 
Compounds of the present invention can be synthesized using the methods 
described below, together with synthetic methods known in the art of 
synthetic organic chemistry, or variations thereon as appreciated by those 
skilled in the art. Preferred methods include, but are not limited to, 
those described below. All references cited herein are hereby incorporated 
in their entirety herein by reference. 
Compounds of this invention of Formula I wherein L.sup.1 is a bond, Z is 
C.dbd.O, and L.sup.2 is a C.sub.2 alkene (Formula Ia) may be prepared, as 
shown in Scheme I, by reacting suitably protected compounds of Formula 
(II) and Formula (III) with a metal hydroxide (MOH) in an appropriate 
solvent at temperatures ranging from 0.degree. to 200.degree. C., followed 
by deprotection. The choice of protecting groups and methods for their 
removal will be apparent to one skilled in the art, as generally described 
in Green, T. and Wuts, P. Protective Groups in Organic Synthesis, 2nd ed.; 
J. Wiley & Sons: New York, 1991. Commonly employed solvents include the 
lower alcohols, such as methanol or ethanol, and N,N-dialkylamides, such 
as N,N-dimethylformamide. Alternatively, a two-phased system consisting of 
water and an immiscible organic solvent, such as dichloromethane, along 
with a phase transfer catalyst, such as a quaternary alkylammonium salt, 
may be used. 
##STR6## 
Compounds of Formula I wherein L.sup.1 is a bond, Z is C.dbd.O, L.sup.2 is 
a C.sub.2 alkene, substituents R.sup.3 and R.sup.4 are sufficiently 
electron withdrawing (e.g. R.sup.3 =H and R.sup.4 =NO.sub.2), and X.dbd.O, 
may be prepared, as shown in Scheme II, by treatment of suitably protected 
compounds of Formula (II) with free phenols of Formula (IV) and an excess 
amount of a metal hydroxide, typically 1.1 to 5 molar equivalents, in a 
solvent, such as methanol or ethanol, followed by an acidic workup to 
yield the intermediate phenol of Formula (V). This phenol (V) may be 
converted to product of Formula (Ib) via either of two alkylation methods, 
followed by final removal of protecting groups. 
In the first alkylation method, the phenol (V) is treated with a base and 
an acid group protected reagent of Formula (VI) bearing a suitable leaving 
group in an appropriate solvent. Suitable bases include, but are not 
limited to, metal carbonates, non-nucleophilic tertiary amines, metal 
hydroxides, and metal hydrides. Typically used solvents are polar in 
nature, such as lower alcohols (methanol or ethanol), lower ketones (such 
as acetone), ethers (such as tetrahydrofuran), sulfoxides (such as 
dimethyl sulfoxide), and N,N-dialkylamides (such as 
N,N-dimethylformamide). Leaving groups G include halogens (especially Br, 
I) and alkyl- or aryl-sulfonates. 
The second type of alkylation involves reaction of the phenol (V) with an 
alcohol of Formula VI (G.dbd.OH) in the presence of an azodicarboxylate 
ester (typically dimethyl, diethyl, or diisopropyl) and a triarylphosphine 
(typically triphenylphosphine) in an inert solvent (such as 
tetrahydrofuran), as generally described by Mitsunobu, O. Synthesis (1981) 
1. 
##STR7## 
An alternate method for the preparation of compounds of Formula I, as shown 
in Scheme III, wherein L.sup.1 is a bond, Z is C.dbd.O, and L.sup.2 is a 
C.sub.2 alkene involves treatment of suitably protected ketones of Formula 
(II) with suitably protected benzaldehydes of Formula (VII), a 
tetraalkoxysilane, typically tetramethoxysilane or tetraethoxysilane in 
the amount of half a molar equivalent, and a metal fluoride, typically 
cesium fluoride or potassium fluoride, in an inert solvent, typically 
N,N-dimethylformamide, at a temperature ranging from around 20.degree. to 
100.degree. C., typically from 60.degree. to 80.degree. C., as has 
generally been described by Chuit et al. Synthesis 1983, 294. The 
resulting enone intermediate is then deprotected to give compound of 
Formula (Ic) according to Green, T. and Wuts, P. Protective Groups in 
Organic Synthesis, 2nd ed.; J. Wiley & Sons: New York, 1991 . 
##STR8## 
Alternatively, compounds of Formula I, wherein L.sup.1 is a bond, Z is 
C.dbd.O, and L.sup.2 is a C.sub.2 alkene, may be prepared, as shown in 
Scheme IV, by treatment of a suitably protected .beta.-ketophosphonate of 
Formula (VIII) with a suitably protected aldehyde or ketone of Formula 
(III) and a strong base in an inert solvent. Deprotection of the resulting 
intermediate yields product of Formula (Id). Appropriate bases include, 
but are not limited to, alkali metal hydrides, such as sodium or potassium 
hydride, alkali metal amides, such as lithium diisopropyl amide or lithium 
or potassium bis(trimethylsilyl)amide, or metal carbonates, such as 
potassium carbonate. Appropriate solvents include ethers, such as 
tetrahydrofuran or dimethoxyethane, N,N-dialkylamides, such as 
N,N-dimethylformamide, lower alkylsulfoxides, such as dimethylsulfoxide, 
lower alkanenitriles, such as acetonitrile, or aromatic hydrocarbons, such 
as benzene, toluene, or xylenes. Reaction temperatures range from about 
-100.degree. to 100.degree. C. 
##STR9## 
Compounds of Formula I, wherein L.sup.1 is a bond, Z is C.dbd.O, and 
L.sup.2 is a C.sub.2 alkene, may also be prepared, as shown in Scheme V, 
by conversion of a suitably protected benzaldehyde of Formula (IX) into an 
oxime of Formula (X) under standard conditions, which is then further 
transformed in situ into a nitrile oxide of Formula (XI) in the presence 
of a styrerie of Formula (XII) to form an isoxazoline of Formula (XIII). 
The isoxazoline (XIII) is then reduced and eliminated to form an enone, 
which after deprotection provides compounds of Formula (Ie). An excellent 
review of the methods and reaction conditions required for the nitrile 
oxide synthesis, its cycloaddition with olefins to form isoxazolines, and 
their reduction and hydrolysis to enones may be found in Torssell, K. B. 
G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH 
Publishers: New York, 1988. 
##STR10## 
Compounds of Formula I wherein L.sup.1 is a C.sub.2 alkene, Z is C.dbd.O, 
and L.sup.2 is a bond may be prepared, as shown in Scheme VI, by treating 
suitably protected compounds of Formula (XIV) and Formula (XV) with a 
metal hydroxide in an appropriate solvent at temperatures ranging from 
0.degree. to 200.degree. C., followed by deprotection. The choice of 
solvent is the same as those described for the synthesis of compounds of 
Formula (Ia) in Scheme I. 
##STR11## 
Compounds of Formula I wherein L.sup.1 is a C.sub.2 alkene, Z is C.dbd.O, 
L.sup.2 is a bond, substituents R.sup.1 and R.sup.2 are sufficiently 
electron withdrawing, n=2-4, and Y=O, may be prepared, as shown in Scheme 
VII, by treating phenols of Formula (XVI) and suitably protected ketones 
of Formula (XV) and an excess amount of a metal hydroxide, typically 1.1 
to 5 molar equivalents, in a solvent, such as methanol or ethanol, 
followed by acidic workup to yield the intermediate phenol of Formula 
(XVII). This phenol (XVII) may be converted to product (Ig) via either of 
two alkylation methods, similar to those described earlier for compound 
(Ib) in Scheme II, using here suitably protected compounds of Formula 
(XVIII), followed by final removal of protecting groups. 
##STR12## 
Alternatively, compounds of Formula I wherein L.sup.1 is a C.sub.2 alkene, 
Z is C.dbd.O, and L.sup.2 is a bond may be prepared, as shown in Scheme 
VIII, by treating suitably protected benzaldehydes of Formula (XIX) with 
suitably protected ketones of Formula (XV), as shown in Scheme VIII, with 
a tetraalkoxysilane, a metal fluoride, and an inert solvent as described 
earlier for the synthesis of compounds (Ic) in Scheme III. 
##STR13## 
Alternatively, compounds of Formula I wherein L.sup.1 is a C.sub.2 alkene, 
Z is C.dbd.O, and L.sup.2 is a bond may be prepared, as shown in Scheme 
IX, by treating suitably protected compounds of Formula (XIV) with a 
.beta.-ketophosphonate of Formula (XX) and a strong base in an inert 
solvent. The selection of base, temperature, and solvent is the same as 
those described for the preparation of compounds of Formula (Id) in Scheme 
IV. 
##STR14## 
Alternatively, compounds of Formula I, wherein L.sup.1 is a C.sub.2 alkene, 
Z is C.dbd.O, and L.sup.2 is a bond, may be prepared, as shown in Scheme 
X, by conversion of a suitably protected benzaldehyde of Formula (XXI) 
into an oxime of Formula (XXII) under standard conditions. This oxime is 
then further transformed, as described earlier for Scheme V, in situ into 
a nit rile oxide of Formula (XXIII) in the presence of a styrene of 
Formula (XXIV) to form an isoxazoline of Formula (XXV). The isoxazoline 
(XXV) is then reduced and eliminated to form an enone, which after 
deprotection provides compounds of type (Ij). 
##STR15## 
Suitably protected compounds of types (Ia-e) may be converted to compounds 
of type (Ik) wherein L.sup.1 is a bond, Z=O, and L.sup.2 is a C.sub.2 
alkyl by selective reduction of the C.dbd.C bond, followed by 
deprotection, as shown in Scheme XI. A host of methods are available for 
this reduction, including hydrogenation by a metal catalyst, dissolving 
metal reductions, and metal hydride additions. The choices of reagents and 
solvents are known to those skilled in the art, as has been reviewed in 
House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin/Cummings: 
Reading, Mass., 1972, and Seyden-Penne, J. Reductions by the Alumino- and 
Borohydrides in Organic Synthesis; VCH Publishers: New York, 1991; pp 
96-100. 
##STR16## 
Compounds of Formula I, wherein L.sup.1 is a C.sub.2 alkyl, Z=O, and 
L.sup.2 is a bond may be prepared by the selective reduction of the 
C.dbd.C bond of suitably protected compounds (If-j), followed by 
deprotection, as shown in Scheme XII. Many methods are available for this 
reduction, including hydrogenation by a metal catalyst, dissolving metal 
reductions, and metal hydride additions, as described for compounds (Il) 
immediately preceeding. 
##STR17## 
Compounds of this invention wherein L.sup.1 is a bond, Z is S(O).sub.p 
where p=0, 1, 2, and L.sup.2 is a C.sub.2 alkene may be prepared, as shown 
in Scheme XIII, by treating suitably protected compounds of Formula (XXVI) 
and Formula (III) in the presence of a strong base in an inert solvent, at 
temperatures from -100.degree. to 200.degree. C. The choice of the 
appropriate base will be known to those skilled in the art, and includes 
alkali metal hydrides, such as sodium or potassium hydride, alkali metal 
amides, such as lithium diisopropyl amide or potassium 
bis(trimethylsilyl)amide, or alkyllithiums, such as n-butyl lithium. 
Useful solvents include, but are not limited to, ethers, such as 
tetrahydrofuran or dimethoxyethane, or aromatic hydrocarbons, such as 
benzene, toluene, or xylenes. Preferred temperatures range from about 
-80.degree. to 110.degree. C. After deprotection, compounds of Formula 
(In) are obtained. 
Those skilled in the art will realize that, in many instances, the 
intermediate hydroxy adduct (XXVII) may be isolated, which must then be 
eliminated to generate the alkene unit. A host of methods are generally 
known in the chemical literature for accomplishing such an elimination, 
such as treatment with a protonic or Lewis acid, or conversion of the --OH 
to a leaving group, such as an alkyl- or aryl-sulfonate, in the presence 
of a suitable base. 
##STR18## 
Compounds of this invention wherein L.sup.1 is a bond, Z is S(O).sub.p 
where p=0, 1, 2, and L.sup.2 is a C.sub.2 alkene may be prepared, as shown 
in Scheme XIV, by treating suitably protected compounds of Formula 
(XXVIII), where Q represents an activating/leaving group such as 
trialkylsilyl, --P(.dbd.O)(alkoxy).sub.2, --P(.dbd.O)(aryl).sub.2, 
--P(aryl).sub.3, --As(aryl).sub.3, or Cl, and Formula (III) in the 
presence of a suitable base in an inert solvent, at temperatures from 
-100.degree. to 200.degree. C. The choice of base includes, but is not 
limited to, alkali metal hydrides, such as sodium or potassium hydride, 
alkali metal amides, such as lithium diisopropyl amide or potassium 
bis(trimethylsilyl)amide, or alkyllithiums, such as n-butyl lithium. 
Useful solvents include, but are not limited to, ethers, such as 
tetrahydrofuran or dimethoxyethane, or aromatic hydrocarbons, such as 
benzene, toluene, or xylenes. After deprotection, compounds of Formula 
(Io) are obtained. 
##STR19## 
Compounds of Formula I, wherein L.sup.1 is a single bond, Z=SO.sub.2, and 
L.sup.2 is a C.sub.2 alkyne, may be prepared, as shown in Scheme XV, by 
treatment of suitably protected compounds of Formula (XXIX) with 
benzaldehydes (VII) in the presence of strong base in an inert solvent, 
conditions which have been generally reported by Lee, J. W.; Kim, T. H.; 
Oh, D. Y. Synth. Commun. 1989, 19, 2633. Deprotection provides product of 
Formula (Ip). 
##STR20## 
Compounds of this invention of Formula (I) wherein L.sup.1 is a bond, Z is 
S(O).sub.p where p=0, and L.sup.2 is a C.sub.1 to C.sub.4 alkyl, 
nonconjugated (to the sulfur atom) C.sub.3 or C.sub.4 alkene or alkyne may 
be prepared, as shown in Scheme XVI, by treating suitably protected 
mercaptans of Formula (XXX) and alkylating agents (XXXI), wherein G is a 
good leaving group, in the presence of a base in an appropriate solvent, 
at temperatures from about -100.degree. to 100.degree. C. The choice of 
the appropriate base will be known to those skilled in the art, and 
includes metal hydroxides, metal alkoxides, metal carbonates, alkali metal 
hydrides, such as sodium or potassium hydride, or alkali metal amides, 
such as lithium diisopropyl amide or potassium bis(trimethylsilyl)amide. 
Useful solvents include, but are not limited to, water, lower alcohols, 
such as methanol or ethanol, ethers, such as tetrahydrofuran or 
dimethoxyethane, N,N-dialkylamides, such as N,N-dimethylformamide, 
sulfoxides, such as dimethylsulfoxide, or aromatic hydrocarbons, such as 
benzene, toluene, or xylenes. Leaving groups G in (XXXI) include halogens 
(especially Br, I), alkyl- or aryl-sulfonates, or 
perfluoroalkylsulfonates. After deprotection, compounds of Formula (Iq) 
are obtained. 
##STR21## 
Compounds of this invention of Formula (I) wherein L.sup.1 is a bond, Z is 
S(O).sub.p where p=1 or 2, and L.sup.2 is a C.sub.1 to C.sub.4 alkyl, 
nonconjugated (to the sulfur atom) C.sub.3 or C.sub.4 alkene or alkyne may 
be prepared, as shown in Scheme XVII, by treating suitably protected 
sulfides (Iq) with an oxidant in an appropriate solvent, followed by 
deprotection. Many methods are known in the chemical literature for the 
oxidation of sulfides to sulfoxides and sulfones, such as are found in the 
recent review by Hudlicky, M. Oxidations in Organic Chemistry; ACS 
Monograph 186; American Chemical Society: Washington, D.C., 1990; pp 
252-262. 
##STR22## 
Compounds of this invention wherein L.sup.1 is a C.sub.2 alkene, Z is 
S(O).sub.p where p=0, 1, or 2, and L.sup.2 is a bond may be prepared, as 
shown in Scheme XVIII, by treating suitably protected compounds of Formula 
(XIV) and Formula (XXXII) in the presence of a strong base in an inert 
solvent, at temperatures from -100.degree. to 200.degree. C. The choice of 
base and solvent are the same as those described for Scheme XIII. Just as 
was described for Scheme XIII, the intermediate hydroxy adduct (XXXIII) 
may be isolated, which must be eliminated to generate the alkene unit. 
After deprotection, compounds of Formula (Is) are obtained. 
##STR23## 
Alternatively, compounds of this invention wherein L.sup.1 is a C.sub.2 
alkene, Z is S(O).sub.p where p=0, 1, or 2, and L.sup.2 is a bond may be 
prepared, as shown in Scheme XIX, by treating suitably protected compounds 
of Formula (XIV) and Formula (XXXIV), where Q represents an 
activating/leaving group such as trialkylsilyl, --P(.dbd.O)(alkoxy).sub.2, 
--P(.dbd.O)(aryl).sub.2, --P(aryl).sub.3, --As(aryl).sub.3, or Cl, in the 
presence of a strong base in an inert solvent, at temperatures from 
-100.degree. to 200.degree. C. The choice of base and solvent are the same 
as those described for Scheme XIV. 
##STR24## 
Compounds of this invention wherein L.sup.1 is a C.sub.2 alkyne, Z is 
SO.sub.2, and L.sup.2 is a bond may be prepared, as shown in Scheme XX, by 
treating suitably protected benzaldehydes of Formula (XIX) and sulfone 
chlorophosphonates of Formula (XXXV) in the presence of a strong base in 
an inert solvent under the Lee conditions cited in the discussion of 
Scheme XV. Final deprotection yields compounds (Iu). 
##STR25## 
Compounds of this invention (I) wherein L.sup.1 is a C.sub.1 to C.sub.4 
alkyl, nonconjugated (to the sulfur atom) C.sub.3 or C.sub.4 alkene or 
alkyne, Z is S (O).sub.p where p=0, and L.sup.2 is a bond, may be 
prepared, as shown in Scheme XXI, by treating suitably protected 
mercaptans of Formula (XXXVI) and alkylating agents (XXXVII), wherein G is 
a good leaving group, in the presence of a base in an appropriate solvent, 
at temperatures from about -100.degree. to 100.degree. C. The choice of 
the appropriate base, solvent, and leaving group G are the same as those 
discussed for Scheme XVI. Deprotection yields compound of Formula (Iv). 
##STR26## 
Compounds of this invention (I) wherein L.sup.1 is a C.sub.1 to C.sub.4 
alkyl, nonconjugated (to the sulfur atom) C.sub.3 or C.sub.4 alkene or 
alkyne, Z is S(O).sub.p where p=1 or 2, and L.sup.2 is a bond may be 
prepared, as shown in Scheme XXII, by treating suitably protected sulfides 
(Iv) with an oxidant in an appropriate solvent, followed by deprotection. 
The methods for the oxidation of sulfides to sulfoxides and sulfones are 
the same as those described for Scheme XVII. 
##STR27## 
Suitably protected compounds of formula (I), where Z is (C.dbd.O), 
SO.sub.2, or (S.dbd.O) may be converted into cyclopropyl compounds of 
formula (Ix), as shown in Scheme XXIII, by treatment with a sulfur ylide, 
such as dimethylsulfonium methylide or dimethylsulfoxonium methylide in a 
suitable solvent, such as DMSO, from about 0.degree. to about 100.degree. 
C. The ylides are prepared in situ from the analogous methylsulf(ox)onium 
salts upon treatment with a strong base, such as sodium hydride. The 
resulting cyclopropane is then deprotected in the usual way to give 
compounds of formula (Ix). 
##STR28## 
Compounds of formula (I) may be prepared, as shown in Scheme XXIV, by the 
Simmons-Smith cyclopropanation of a suitably protected alkene, typically 
using CH.sub.2 I.sub.2 and Zn dust in an inert solvent, such as diethyl 
ether, from around room temperature to around 50.degree. C. The 
cyclopropane product is then deprotected in the usual way to give 
compounds of formula (Iy). 
##STR29## 
Certain compounds of formula (I) may be prepared as shown in Scheme XXV. A 
suitably protected 6-bromo-naphthol of formula (XXXIX) is converted to its 
corresponding naphthyllithium by treatment with a metallating agent, such 
as n-butyllithium, in an inert solvent, such as tetrahydrofuran, at low 
temperature, typically about -100.degree. C. to about 0.degree. C. The 
resulting lithiated naphthol intermediate is allowed to react with a 
suitably protected compound of formula XIV (where D is (C.dbd.O)R.sup.5) 
or formula XXXVIII (where D is CN), at temperatures ranging from 
-100.degree. C. to 100 .degree. C. After aqueous work-up, a ketone bridge 
is formed from D.dbd.CN, while an alcohol is generated from 
D=(C.dbd.O)R.sup.5. In those instances where the alcohol is formed, it 
must then be oxidized by any of a multitude of methods such as a Swern 
oxidation, into the ketone. The hydroxyl protecting group P' is then 
cleaved under the appropriate conditions to produce the naphthol. The 
naphthol is then allowed to react with a compound of formula (VI) as has 
been described earlier for the analogous phenolic alkylation in Scheme II. 
Final deprotection in the usual way provides compounds of formula (Iz). 
##STR30## 
Certain compounds of formula (I) may be prepared as shown in Scheme XXVI. A 
suitably protected phenyl tributylstannane of formula (XL) is allowed to 
react with a suitably protected compound of formula (XLI), wherein E may 
be Br, I, OSO.sub.2 CF.sub.3 or (C.dbd.O)Cl, in an inert solvent, such as 
toluene or benzene, under an atmosphere of carbon monoxide at elevated 
temperature in the presence of an appropriate palladium (0) catalyst, such 
as tetrakis (triphenylphosphine) palladium (0). The resulting ketone of 
formula (XLII) is converted to the target compound of formula (Iaa) via 
the same sequence of steps as described in Scheme XXV. 
The following examples further illustrate details for the preparation of 
the compounds of the present invention. Those skilled in the art will 
readily understand that known variations of the conditions and processes 
of the following preparative procedures can be used to prepare the 
compounds of the present invention. All temperatures are degrees Celsius 
unless otherwise noted. 
EXAMPLES 
Representative examples were prepared by the methods set forth below. 
Example 1 
(E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]phenoxyacetic 
acid.multidot.hydrochloride. 
1a) 3'-(2-Hydroxyethoxy)acetophenone 
3'-Hydroxyacetophenone (5.0 g, 37 mmol), potassium carbonate (6.1 g, 44 
mmol), sodium iodide (0.28 g, 1.8 mmol), and 2-bromoethanol (2.6 mL, 37 
mmol) were stirred in N,N-dimethylformamide (DMF) for 20 h at room 
temperature, then for 4 days at 70.degree.-80.degree. C. The reaction 
mixture was diluted with ethyl acetate (EtOAc) and extracted several times 
with water, then dried over magnesium sulfate (MgSO.sub.4), and 
concentrated in vacuo. Chromatography on silica gel, eluting with 30% to 
50% EtOAc in hexanes, after solvent removal, gave a viscous oil (2.1 g). 
.sup.1 H-NMR(300 MHz, CDCl.sub.3): 7.56(d, 1H, J=8 Hz), 7.51(s, 1H), 
7.39(t, 1H, J=8 Hz), 7.14(d, 1H, J=8 Hz), 4.14 (m, 2H), 3.99 (m, 2H), 2.60 
(s, 3H), 2.09 (br, 1H). 
1b) 3'-(2-p-Toluenesulfonyloxyethoxy)acetophenone 
A solution of p-toluenesulfonic anhydride (3.6 g, 11 mmol) in 
dichloromethane (CH.sub.2 Cl.sub.2, 36 mL) was added dropwise over 1 h to 
a solution of 3'-(2-hydroxyethoxy)acetophenone (1.5 g, 8.3 mmol) and 
triethylamine (1.7 mL, 12 mmol) in CH.sub.2 Cl.sub.2 (76 mL). After 
stirring at room temperature overnight, the solvent was evaporated in 
vacuo. The residue was extracted with water, 1 M hydrochloric acid, 
saturated aqueous sodium bicarbonate, and brine. Drying (MgSO.sub.4), and 
solvent removal gave the crude tosylate as a gum (2.9 g), which was not 
purified. .sup.1 H-NMR(300 MHz, CDCl.sub.3): 7.8 (d, 2H), 7.55 (d, 1H), 
7.4 (m, 4H), 7.0 (d, 1H), 4.4 (m, 2H), 4.2 (m, 2H), 2.6 (s, 3H), 2.45 (s, 
3H). 
1c) 3'-[2-(N,N-Bis-t-butyloxycarbonyl)aminoethoxy]acetophenone 
Crude tosylate 1b (2.9 g, 8.3 mmol) and di-t-butyliminodicarboxylate, 
potassium salt (2.2 g, 8.4 mmol) were stirred in DMF at room temperature 
for 65 h, then diluted with EtOAc and extracted several times with water. 
After drying (MgSO.sub.4) and solvent removal, the product was 
chromatographed on silica gel, eluting with 20-40% EtOAc in hexanes. 
Solvent removal gave an oil (3.2 g). .sup.1 H-NMR (300 MHz, CDCl.sub.3): 
7.54 (d, 1H, J=8 Hz), 7.47 (m, 1H), 7.36 (t, 1H, J=8 Hz), 7.10 (m, 1H), 
4.18 (t, 2H, J=6 HZ), 4.03 (t, 2H, J=6 HZ), 2.59 (s, H), 1.51 (s, 18H). 
1d) 
4-[3-((3-(2-t-Butyloxycarbonylaminoethoxy)phenyl))-3-oxo-1-propenyl]phenox 
yacetic acid 
The N-protected acetophenone 1c (1.5 g, 3.9 mmol), 4-formylphenoxyacetic 
acid (0.70 g, 3.9 mmol), and sodium hydroxide (0.32 g, 8.0 mmol) were 
heated at reflux in methanol (30 mL) for 8 days. After cooling and solvent 
removal, the residue was extracted with EtOAc and 5% aqueous KHSO.sub.4. 
After drying (MgSO.sub.4) and solvent removal, the product was 
chromatographed on silica gel, eluting with 10-20% methanol in chloroform. 
Solvent removal gave a solid (0.77 g). .sup.1 H-NMR (300 MHz, d.sub.6 
-DMSO): 7.79 (d, 2H, J=8 Hz), 7.71 (m, 3H), 7.58 (s, 1H), 7.46 (m, 1H), 
7.21 (d, 1H, J=8 Hz), 7.05 (br, 1H), 6.90 (d, 2H, J=9 Hz), 4.35 (s, 2H), 
4.04 (m, 2H), 3.33 (m, 2H), 1.38 (s, 9H). HR-MS: Calc. 442.1866, Found 
442.1860. 
1e) (E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]phenoxyacetic 
acid.multidot.hydrochloride 
A mixture of N-BOC amine 1d (0.20 g, 0.45 mmol) and 4 M hydrogen chloride 
in 1,4-dioxane (1.0 mL) was stirred at room temperature under a CaSO.sub.4 
drying tube for 3.3 h. Dilution with diethyl ether produced a precipitate, 
which was collected by filtration and dried to give a yellow powder (0.17 
g). .sup.1 H-NMR(300 MHz, d.sub.6 -DMSO): 13.1 (br, 1H), 8.09 (br, 3H), 
7.87-7.82 (m, 3H), 7.78 and 7.74 (AB quartet, 2H, J=15 Hz), 7.63 (s, 1H), 
7.53 (t, 1H, J=8 Hz), 7.28 (dd, 1H, J=8,2 Hz), 7.01 (d, 2H, J=9Hz), 4.78 
(s, 2H), 4.30-4.26 (m, 2H), 3.36 (br, 2H). HR-MS: Calc. 342.1341, Found 
342.1349. IR(KBr) cm.sup.-1 3398, 1744, 1656. 
Example 2 
(E)-Ethyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate.multidot.trifluoroacetate 
2a) Methyl 3-[2-(t-butyloxycarbonylamino)ethoxy]benzoate 
Methyl 3-hydroxybenzoate (1.0 g, 6.7 mmol), N-BOC-2-aminoethanol (1.0 g, 
6.7 mmol), triphenylphosphine (1.8 g, 6.7 mmol), and 
diisopropylazodicarboxylate (1.4 mL, 6.7 mmol) were stirred in 
tetrahydrofuran (THF) at -20.degree. C. under nitrogen for around 6 hours, 
then at room temperature overnight. After removal of solvent in vacuo, the 
mixture was chromatographed on silica gel, eluting with 0% to 35% EtOAc in 
hexanes. Removal of solvent gave a pale yellow, viscous oil (1.9 g) which 
was contaminated with a small amount of the unreacted starting phenol. 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): 7.67-7.08 (m, 4H), 5.16 (br, 1H), 4.07 
(t, 2H, J=5 Hz), 3.92 (s, 3H), 3.58-3.53 (m, 2H), 1.46 (s, 9H). IR(neat) 
cm.sup.-1 3376,l 1722. 
2b) Dimethyl 
2-[3-((2-(N-t-butyloxycarbonyl)aminoethoxy))phenyl]-2-oxo-ethylphosphonate 
Diisopropylamine (1.4 mL, 10 mmol) was added dropwise via syringe over 3 
min to a solution of n-butyllithium (1.6 M in hexanes, 5.8 mL, 9.2 mmol) 
in dry THF at -60.degree. C. with stirring under nitrogen. After 15 min, a 
solution of dimethyl methylphosphonate (0.66 mL, 6.1 retool) in THF (5 mL) 
was added via cannula. After 10 min, a solution of methyl ester 2a (1.8 g, 
6.1 mmol) in THF (5 mL) was introduced via cannula over about 1 min. After 
stirring for another 10 rain at -60.degree. C., the cold bath was replaced 
with an ice water bath. After 20 min, the reaction was quenched by adding 
1 M HCl (20 mL). The mixture was immediately extracted with EtOAC. The 
organic layer was extracted further with water (2.times.), then brine, and 
dried (MgSO.sub.4). After solvent removal, the crude product was 
chromatographed on silica gel, eluting with EtOAc. Solvent removal gave a 
viscous yellow oil (0.76 g). .sup.1 H-NMR(300 MHz, CDCl.sub.3): 7.60 (dr, 
1H, J=8, 1 Hz), 7.53 (t, 1H, J=3 Hz), 7.40 (t, 1H, J=8 Hz), 7.14 (ddd, 1H, 
J=8,3,1 Hz), 5.00 (br, 1H), 4.10-4.06 (m, 2H), 3.79 (d, 6H, J=11 Hz), 3.63 
(d, 2H, J=23 Hz), 3.58-3.52 (m, 2H), 1.45 (s, 9H). Anal. Calc'd for 
C.sub.17 H.sub.26 NO.sub.7 P: C, 52.71; H, 6.77; N, 3.62; Found: C, 52.49; 
H, 6.97; N, 3.35. 
2c) Ethyl 5-formyl-2-hydroxybenzoate 
5-Formylsalicylic acid (3.0 g, 17 mmol), conc. sulfuric acid (1 mL) and 
absolute ethanol (100 mL) were heated at reflux for 3.5 days with stirring 
under N.sub.2. The reaction was cooled, then carefully quenched by adding 
saturated sodium bicarbonate (40 mL). Solvent was removed in vacuo, and 
the resulting mixture was acidified with 1 M HCl (50 mL), then extracted 
with EtOAc. The organic phase was extracted with water, then brine, and 
dried (MgSO.sub.4). Removal of solvent and chromatography on silica gel, 
eluting with 0% to 25% EtOAc in hexanes gave a colorless crystalline solid 
(2.3 g), mp 67.degree.-69.degree. C., after solvent removal. .sup.1 
H-NMR(300 MHz, CDCl.sub.3): 11.49 (s, 1H), 9.90 (s, 1H), 8.40 (d, 1H, J=2 
Hz), 8.00 (dd, 1H, J=8,2 Hz), 7.11 (d, 1H, J=8 Hz), 4.48 (q, 2H, J=7 Hz), 
1.46 (t, 3H, J=7 Hz). IR (KBr): cm.sup.-1 3186, 1684. 
2d) Ethyl 2-[2-(t-butyloxy)-2-oxo-ethoxy]-5-formylbenzoate 
Phenol 2c (1.0 g, 5.2 mmol), t-butyl bromoacetate (0.84 mL, 5.2 mmol), and 
potassium carbonate (0.79 g, 5.7 mmol) were heated at 65.degree. C. in DMF 
(8 mL) overnight. After solvent removal, the mixture was diluted with 
EtOAc and extracted with water (3.times.), then brine. Drying (MgSO.sub.4) 
and removal of solvent gave a clear yellow oil (1.56 g). .sup.1 H-NMR(300 
MHz, CDCl.sub.3): 9.93 (s, 1H), 8.35 (d, 1H, J=2 Hz), 7.99 (dd, 1H, J=9,2 
Hz), 6.95 (d, 1H, J=9 Hz), 4.71 (s, 2H), 4.41 (q, 2H, J=7 Hz), 1.48 (t, 
3H, J=7 Hz). Anal. Calc'd for C.sub.16 H.sub.20 O.sub.6 : C, 62.33; H, 
6.54; Found: C, 62.05; H, 6.58. 
2e) (E)-Ethyl 
5-[3-((3-(2-t-butyloxycarbonylamino)-ethoxyphenyl))-3-oxo-1-propenyl]-2-[2 
-(t-butyloxy]-2-oxo]ethoxybenzoate 
Sodium hydride (60% oil disp., 26 mg, 0.65 mmol) was added to a solution of 
.beta.-ketophosphonate 2b (0.25 g, 0.65 mmol) and aldehyde 2d (0.20 g, 
0.65 mmol) in dry THF (5 mL) with stirring at room temperature. After 19 
h, solvent was removed under a rapid stream of N.sub.2. The mixture was 
diluted with EtOAc and extracted with water (2.times.), then brine, and 
dried (MgSO.sub.4). After solvent removal, the residue was chromatographed 
on silica gel, eluting with 0% to 50% EtOAc in hexanes. After solvent 
removal, a yellow gum (0.24 g) was obtained. .sup.1 H-NMR (300 MHz, 
CDCl.sub.3): 8.12 (d, 1H, J=2 Hz), 7.77 (d, 1H, J=16 Hz), 7.71 (dd, 1H, 
J=9,2 Hz), 7.62 (d, 1H, J=8 Hz), 7.54-7.52 (m, 1H), 7.43 (d, 1H, J=16 
Hz), 7.42 (t, 1H, J=8 Hz), 7.13 (dd, 1H, J=8,2 Hz), 6.89 (d, 1H, J=9 Hz), 
5.00 (br, 1H), 4.66 (s, 2H), 4.42 (q, 2H, J=7 Hz), 4.13-4.09 (m, 2H), 
3.60-3.55 (m, 2H), 1.49 (s, 9H). MS(NH.sub.3): 587 (base, M+NH.sub.4). 
2f) (E)-Ethyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate .multidot.trifluoroacetate 
Trifluoroacetic acid (1 mL) was added to a solution of substrate 2e (0.24 
g, 0.42 mmol) in dichloromethane (3 mL) with stirring at room temperature 
under a CaSO.sub.4 tube. After 80 minutes, diethyl ether was added, which 
led to precipitate formation. The precipitate was collected by filtration 
and dried under high vacuum to give a yellow powder (0.17 g). .sup.1 H-NMR 
(300 MHz, d.sub.6 -DMSO): 8.10 (d, 1H, J=2 Hz), 7.97 (dd, 1H, J=9, 2 Hz), 
7.87-7.80 (m, 3H), 7.72 (d, 1H, J=16 Hz), 7.61 (br s, 1H), 7.53 (t, 1H, 
J=8 Hz), 7.28 (dd, H, J=8,2 Hz), 7.03 (d, 1H, J=9 Hz), 4.68 (s, 2H), 
4.33-4.24 (m, 4H), 3.25 (m, 2H), 1.32 (t, 3H, J=7 Hz). IR(KBr): cm.sup.-1 
3300-2300, 1736, 1686, 1658. 
Example 3 
(E)-Ethyl 5-[3-((2-(1-prop-2-enyloxy)- 
5-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethozy)benzoate.mul 
tidot.trifluoroacetate. 
3a) Methyl 2,5-dihydroxybenzoate 
2,5-Dihydroxybenzoic acid was converted to its methyl ester using catalytic 
sulfuric acid in methanol following the same protocol as for 
esterification 2c in 94% yield. mp 86.4.degree.-88.5.degree. C. IR(KBr): 
cm.sup.-1 3346, 1684. 
3b) Methyl 5-(2-t-butyloxycarbonylamino) ethoxy-2-hydroxybenzoate 
Methyl 2,5-dihydroxybenzoate was converted to its 5-(N-BOC-aminoethoxy) 
adduct following the Mitsunobu coupling protocol used in the preparation 
of 2a (53% yield). .sup.1 H-NMR (300 MHz, CDCl.sub.3): 90% pure, 10.38 (s, 
H), 7.28 (d, 1H, J=3 Hz), 7.06 (dd, 1H, J=9, 3 Hz), 6.90 (d, 1H, J=9 Hz), 
5.00 (br, 1H), 3.97 (t, 2H, J=5 Hz), 3.94 (s, 3H), 3.50 (m, 2H), 1.44 (s, 
9H). 
3c) Methyl 5-(2-t-butyloxycarbonylamino)ethoxy-2-(1-prop-2-enyloxy)benzoate 
Phenol 3b (3.94 g, 12.7 mmol), allyl bromide (1.2 mL, 14 mmol), and 
potassium carbonate (1.95 g, 14 mmol) were heated to 
45.degree.-55.degree. C. in DMF. After 4 days, TLC indicated incomplete 
reaction, so more allyl bromide was added (0.5 mL). After 3 more days, 
still more allyl bromide (0.75 mL) was added. The next day, the reaction 
was worked up and chromatographed on silica gel, eluting with 0% to 40% 
EtOAc in hexanes. After removal of solvent, an oil (2.7 g) was obtained. 
.sup.1 H-NMR(300 MHz, CDCl.sub.3): 7.34 (d, 1H, J=3 Hz), 7.00 (dd, 1H, 
J=9,3 Hz), 6.92 (d, 1H, J=9 Hz), 6.12-6.00 (m, 1H), 5.51-5.27 (m, 2H), 
4.98 (br, 1H), 4.59-4.56 (m, 2H), 4.00 (t, 2H, J=5 Hz), 3.90 (s, 3H), 
3.55-3.51 (m, 2H), 1.45 (s, 9H). HR-MS: Calc'd. 369.2026, Found 369.2014. 
3d) Dimethyl 
2-[3-((2-(N-t-butyloxycarbonylamino)ethoxy))-2-(1-prop-2-enyloxy)phenyl]-2 
-oxo-ethylphosphonate 
Methyl ester 3c was converted to a dimethyl .beta.-ketophosphonate 
according to the procedure used for the synthesis of 2b in 46% yield as an 
oil. .sup.1 H-NMR(300 MHz, CDCl.sub.3): 7.27 (d, 1H, J=2 Hz), 7.03 (dd, 
1H, J=9,2 Hz), 6.90 (d, 1H, J=9 Hz), 6.13-6.04 (m, 1H), 5.44-5.31 (m, 2H), 
4.90 (br, 1H), 4.62 (d, 2H, J=6 Hz), 3.99 (t, 2H, J=5 Hz), 3.88 (d, 2H, 
J=21 Hz), 3.75 (d, 6H, J=11 Hz), 3.54-3.49 (m, 2H), 1.45 (s, 9H). HR-MS: 
Calc'd. 461.2053, Found 461.2063. 
3e) (E)-Ethyl 
5-[3-((5-(2-t-butyloxycarbonylamino)-ethoxy-2-(1-prop-2-enyloxy)phenyl))-3 
-oxo-1-propenyl]-2-[2-(t-butyloxy)-2-oxo]ethoxybenzoate 
Aldehyde 2d and .beta.-ketophosphonate 3d were condensed using the 
conditions described for the synthesis of 2e to give a yellow oil in 20% 
yield. HR-MS: Calc'd. 626.2965, Found 626.2964. 
3f) (E)-Ethyl 
5-[3-((2-(1-prop-2-enyloxy)-5-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2- 
(carboxymethoxy)benzoate.multidot.trifluoroacetate 
Chalcone 3e was deprotected using trifluoroacetic acid in CH.sub.2 Cl.sub.2 
as described for 2f to yield a yellow solid (76%). HR-MS: Calc'd. 
470.1815, Found 470.1810. 
Example 23 
(E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-methoxyphenoxyacet 
ic acid.multidot.trifluoroacetate 
23a) 3-Methoxy-4-(2-t-butyloxy-2-oxo-ethoxy)benzaldehyde 
Vanillin was alkylated with t-butyl bromoacetate in DMF in the presence of 
potassium carbonate the usual way to give a waxy solid. (quant.) mp 
86.8.degree.-90.degree. C. MS(NH.sub.3): 284 (base, M+NH.sub.4). 
23b) (E)-t-Butyl 
4-[3-((3-(2-t-butyloxycarbonylamino)-ethoxyphenyl))-3-oxo-1-propenyl]-2-me 
thoxyphenoxyacetate 
A solution of potassium t-butoxide in t-butanol (1 M, 1.3 mL, 1.3 mmol) was 
added dropwise to a stirred solution of .beta.-ketophosphonate 2b (0.50 g, 
1.3 mmol) in dry THF (20 mL) at room temperature. After 2 h, aldehyde 5a 
(0.34 g, 2.6 mmol) was added. After stirring overnight, the reaction was 
quenched with 5% aq. KHSO.sub.4, then extracted with EtOAc. The organic 
layer was further extracted with water, then dried (Na.sub.2 SO.sub.4) and 
concentrated. The product was purified by chromatography on silica gel, 
eluting with 0% to 40% EtOAc in hexanes. After solvent removal, a yellow 
oil was obtained (0.16 g). MS (NH.sub.3): 545 (M+NH.sub.4), 528 (M+H). 
23c) 
(E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-methoxyphenoxyace 
tic acid.multidot.trifluoroacetate 
Substrate 23b was deprotected with trifluoroacetic acid/dichloromethane in 
the usual way to give a yellow solid (0.12 g). MS(NH.sub.3): 372 (base, 
M+H). mp. 195.degree.-198.degree. C. 
Example 24 
(E)-n-Butyl 
5-[3-((3-(2-aminoethoxy)-phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benz 
oate.multidot.trifluoroacetate 
24a) n-Butyl 5-formyl-2-hydroxybenzoate 
5-Formylsalicylic acid (5.0 g, 30 mmol), n-butyl iodide (3.4 mL, 30 mmol), 
and potassium carbonate (4.2 g, 30 mmol) were stirred in DMF (40 mL) for 
27 h at room temperature. After several EtOAc/H.sub.2 O extractions, the 
mixture was dried (MgSO.sub.4), and concentrated. Chromatography on silica 
gel, eluting with 5% to 30% EtOAc in hexanes, followed by solvent removal 
gave a white solid (2.0 g). HR-MS: Calc'd 223.0970, Found 223.0968. Anal. 
Calc'd for C.sub.12 H.sub.14 O.sub.4 : C, 64.84; H, 6.36; Found: C, 64.82; 
H, 6.30. 
24b) (E)-n-Butyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate .multidot.trifluoroacetate 
Phenol 24a was converted, via the usual sequence of steps, into final 
product 24b as a solid. HR-MS: Calc'd 442.1866, Found 442.1851. 
Example 36 
(E)-Methyl 
5-[3-((3-(2-aminoethoxy)-phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)-3-( 
1-prop-2-enyl)benzoate .multidot.trifluoroacetate 
36a) Methyl 5-formyl-2-(1-prop-2-enyloxy)benzoate 
Methyl 5-formylsalicylate (3.3 g, 18 mmol), allyl bromide (1.7 mL, 20 
mmol), and potassium carbonate (2.8 g, 20 mmol) were stirred at room 
temperature in DMF (20 mL) overnight. After concentration, the mixture was 
diluted with EtOAc and extracted with water (5.times.), then brine. After 
drying (MgSO.sub.4), solvent was removed to give a yellow solid (4.2 g). 
.sup.1 H-NMR(300 MHz, CDCl.sub.3): 9.92 (s, 1H), 8.35 (d, 1H, J=2 Hz), 
8.00 (dd, 1H, J=9,2 Hz), 7.09 (d, 1H, J=9 Hz), 6.13-6.01 (m, 1H), 
5.58-5.34 (m, 2H), 4.75-4.73 (m, 2H), 3.93 (s, 3H). Anal. Calc'd for 
C.sub.12 H.sub.12 O.sub.4 : C, 65.45; H, 5.49; Found: C, 65.10; H, 5.36. 
36b) Methyl 5-formyl-2-hydroxy-3-(1-prop-2-enyl)benzoate 
Allyl ether 36a was heated neat to ca. 175.degree. C. overnight with 
stirring under N.sub.2. After cooling, the product was purified by 
chromatography on silica gel, eluting with 0% to 30% EtOAc in hexanes. 
Solvent was removed to give a yellow oil (50% yield). .sup.1 H-NMR(300 
MHz, CDCl.sub.3) : 11.68 (s, 1H), 9.85 (s, 1H), 8.27 (d, 1H, J=2 Hz ), 
7.88-7.87 (m, 1H), 6.06-5.92 (1H), 5.14-5.08 (m, 2H), 3. 99 (s, 3H), 3.46 
(d, 2H, J=7 Hz ). Anal. Calc'd for C.sub.12 H.sub.12 O.sub.4 : C, 65.45; 
H, 5.4 9; Found: C, 65.54; H, 5.49. 
36c) Methyl 
5-formyl-2-(2-t-butyloxy-2-oxo-ethoxy)-3-(1-prop-2-enyl)benzoate 
Phenol 36b was alkylated with t-butyl bromoacetate the usual way to give a 
yellow oil (quant.). .sup.1 H-NMR (300 MHz, CDCl.sub.3): 9.94 (s, 1H), 
8.21 (d, 1H, J=2 Hz), 7.90 (d, 1H, J=9 Hz), 6.05-5.92 (m, 1H), 5.15-5.05 
(m, 2H), 4.51 (s, 2H), 3.93 (s, 3H), 3.61 (br d, 2H, J=7 Hz), 1.49 (s, 
9H). Anal. Calc'd for C.sub.18 H.sub.22 O.sub.6 : C, 64.66; H, 6.63; 
Found: C, 64.54; H, 6.62. 
36d) (E)-Methyl 
5-[3-((3-(2-t-butyloxycarbonylamino-ethoxy)phenyl))-3-oxo-1-propenyl]-2-[2 
-(t-butyloxy)-2-oxo-ethoxy]-3-(1-prop-2-enyl)benzoate 
Methyl ketone 1c (0.28 g, 1.0 mmol), aldehyde 36c (0.34 g, 1.0 mmol), 
potassium fluoride (freshly dried, 58 mg, 1.0 mmol), and 
tetramethylorthosilicate (74 .mu.L, 0.50 mmol) were heated under nitrogen 
in dry DMF (2 mL) at room temperature for 2 days and then at 70.degree. C. 
for 2 days. After cooling, the mixture was extracted with EtOAc and water 
(5.times.), then brine. After drying (MgSO.sub.4), solvent was removed and 
the product was chromatographed on silica gel, eluting with 0% to 35% 
EtOAc in hexanes. Removal of solvent gave a yellow foam (0.20 g). 
MS(NH.sub.3): 613 (base, M+NH.sub.4). 
36e) (E)-Methyl 
5-[3-((3-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)-3-(1 
-prop-2-enyl) benzoate.multidot.trifluoroacetate 
Substrate 36d was deprotected in the usual way to give a yellow powder 
(85%). .sup.1 H-NMR(300 MHz, d.sub.6 -DMSO): 8.09 (d, 1H, J=2Hz), 
7.99-7.87 (m, 6H), 7.73 (d, 1H, J=16 Hz), 7.63 (br s, 1H), 7.55 (t, 1H, 
J=8 Hz), 7.31 (dd, 1H, J=8, 3Hz), 6.11-5.97 (m, 1H), 5.11-5.06 (m, 2H), 
4.52 (s, 2H), 4.28-4.25 (m, 2H), 3.86 (s, 3H), 3.54 (d, 2H, J=7 Hz), 
3.30-3.25 (m, 2H). Anal. Calc'd for C.sub.26 H.sub.26 F.sub.3 NO.sub.9 
.multidot.H.sub.2 O: C, 54.64; H, 4.94; N, 2.45; F, 9.97; Found: C, 54.87; 
H, 4.66; N, 2.48; F, 10.05. 
Example 76 
(E)-4-[3-((3-(Aminomethyl)phenyl))-3-oxo-1-propenyl]benzene-1,2-bis 
(oxyacetic acid) .multidot.trifluoroacetate. 76a) 
3,4-Bis-(2-t-butyloxy-2-oxo-ethoxy)benzaldehyde 
3,4-Dihydroxybenzaldehyde (10 g, 7.2 mmol), t-butyl bromoacetate (32 mL, 20 
mmol, added in portions over 3 days), and potassium carbonate (22 g, 16 
mmol) were heated in DMF (75 mL) to 60.degree.-65.degree. C. for 4 days. 
After the usual work-up, the product was chromatographed on silica gel, 
eluting with 0% to 25% EtOAc in hexanes. 
Solvent was removed in vacuo to give a pale yellow solid (13.6 g). top. 
90.5.degree.-93.7.degree. C. HR-MS: Calc'd 384.2022, Found 384.2014. 
76b) Methyl 3-[(N,N-bis-t-butyloxycarbonyl)aminomethyl]benzoic acid 
Methyl 3-(bromomethyl) benzoate (10 g, 44 mmol) and 
di-t-butyliminodicarboxylate, potassium salt (11.4 g, 44 mmol) were 
stirred at room temperature in DMF for 3.5 h. The mixture was diluted with 
EtOAc and extracted with water (3.times.), then brine. After drying 
(MgSO.sub.4), solvent was removed in vacuo to give a clear oil (15.5 g). 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): 7.99 (s, 1H), 7.94 (d, 1H, J=8 Hz), 
7.50 (d, 1H, J=8Hz), 7.39 (t, 1H, J=8 Hz), 4.82 (s, 2H), 3.91 (s, 3H), 
1.47 (s, 18H). MS (NH3): 383 (base, M+NH.sub.4). 76c) 
(E)-4-[3-((3-(Aminomethyl)phenyl))-3-oxo-1-propenyl]benzene-1,2-bis(oxyace 
tic acid).multidot.trifluoroacetate 
Methyl ester 76b was converted to the .beta.-ketophosphonate, coupled with 
aldehyde 76a, and deprotected via the usual methods to give a yellow 
solid. IR (KBr) cm.sup.-1 3400-2700, 1732, 1662. FAB-HR-MS(glycerol): 
Calc'd 386.1240, Found 386.1250. 
Example 91 
(E)-4-[3-((3-(2-Aminoethyl)phenyl))-3-oxo-1-propenyl]-2-ethoxyphenoxyacetic 
acid.multidot.trifluoroacetate. 
91a) Methyl 3-(cyanomethyl)benzoate 
Methyl 3-(bromomethyl) benzoate (8.5 g, 37 mmol) and sodium cyanide (1,8 g, 
37 mmol) were stirred at room temperature in DMF (40 mL) overnight. The 
mixture was diluted with EtOAc and extracted several times with water 
containing a small amount of brine, then brine, dried (MgSO.sub.4), and 
solvent removed in vacuo. The crude product (6.8 g, yellow oil) was 
sufficiently pure to be used in the next step without purification. 
IR(neat): cm.sup.-1 2249, 1722. .sup.1 H-NMR(300 MHz, CDCl.sub.3): 
8.03-8.01 (m, 2H), 7.57-7.46 (m, 2H), 3.94 (s, 3H), 3.82 (s, 2H). 
91b) Methyl 3-(2-aminoethyl)benzoate.multidot.p-toluenesulfonate 
Nitrile 91a (4.8 g, 27 mmol) was hydrogenated on a Parr shaker at 40 psi 
H.sub.2 in the presence of 10% Pd/C (0.48 g) and p-toluenesulfonic acid 
(5.2 g, 27 mmol) in methanol (100 mL). The solution was filtered through a 
Celite pad to remove the catalyst, then solvent was removed in vacuo to 
give an orange solid (10.7 g). HR-MS: Calc'd. 180.1025. Found 180.1025. 
91c) Methyl 3-(2-t-butyloxycarbonylaminoethyl)benzoate 
Amine salt 91b (12.5 g, 34 mmol), triethylamine (4.7 mL, 34 mmol), and 
di-t-butyl-dicarbonate (7.4 g, 34 mmol) were stirred in methanol (150 mL) 
for 5 h at room temperature. After solvent removal, the residue was 
diluted with EtOAc and extracted with water (2.times.), then brine. Drying 
(MgSO.sub.4) and solvent removal gave an oil (9.3 g). .sup.1 H-NMR(300 
MHz, CDCl.sub.3): 7.92-7.88 (m, 2H), 7.40-7.38 (m, 2H), 3.92 (s, 3H), 
3.41-3.36 (m, 2H), 2.86 (t, 2H, J=7 Hz), 1.43 (s, 9H). 
91d) 4-Formyl-2-ethoxyphenoxyacetic acid 
4-Hydroxy-3-ethoxybenzaldehyde (5.0 g, 36 mmol), potassium carbonate (5.0 
g, 36 mmol), and t-butyl bromoacetate (5.9 mL, 36 mmol) were heated to 
55.degree. C. overnight in DMF (35 mL). After removal of solvent, the 
mixture was extracted with EtOAc and water, then brine. After drying 
(Na.sub.2 SO.sub.4), solvent was removed to yield a white solid (9.7 g). 
mp 90.degree.-92.6.degree. C. MS (NH.sub.3): 298 (base, M+NH.sub.4). 
91e) 
(E)-4-[3-((3-(2-Aminoethyl)phenyl))-3-oxo-1-propenyl]-2-ethoxyphenoxyaceti 
c acid.multidot.trifluoroacetate 
The N-BOC methyl ester 91c was converted to a .beta.-ketophosphonate in the 
usual manner, then coupled to aldehyde 91d and deprotected as previously 
described to give a yellow solid. HR-MS: Calc'd 370.1654, Found 370.1646. 
Example 112 
(E)-4-[3((3-(guanidinylmethyl)phenyl))-3-oxo-1-propenyl]-2-methoxyphenoxyac 
etic acid.multidot.trifluoroacetate. 
112a) Methyl 3-((N,N-bis-(t-butyloxycarbonyl)aminomethyl))benzoate 
Methyl 3-bromomethylbenzoate (10 g, 44 mmol) and (BOC).sub.2 NK (11.4 g, 44 
mmol) were stirred in DMF (40 mL) for 3 h at room temperature. The mixture 
was diluted with EtOAc and extracted with water (3.times.), then brine. 
Drying (Na.sub.2 SO.sub.4), filtration, and evaporation yielded a clear 
oil (15.5 g) which was sufficiently pure for use in the next step. 
IR(film) cm.sup.-1 1791, 1726. .sup.1 H NMR(300 MHz, CDCl.sub.3): 
7.99-7.39 (m, 4H), 4.82 (s, 2H), 3.91 (s, 3H), 1.47 (s, 18H). MS (NH3): 
383 (base, M+NH.sub.4), 327 (32%), 283 (8%). 
112b) Dimethyl 
2-((3-(N-t-butyloxycarbonyl)aminomethyl))phenyl-2-oxo-ethylphosphonate 
Diisopropylamine (8.0 mL, 57 mmol) was added dropwise over 6 min to a -65 
.degree. C. solution of n-butyllithium (35 mL, 56 mmol, 1.6 M in hexanes) 
in dry THF (200 mL). After 0.5 h, a solution of dimethyl methylphosphonate 
(3.0 mL, 28 mmol) in dry THF (30 mL) was added over 8 min. After 2.75 h at 
-65 .degree. C., a solution of ester 112a (10 g, 27 mmol) in dry THF (70 
mL) was added over 45 min. The mixture was stirred for an additional 45 
rain at -65 .degree. C., then for 3 h at 0.degree.-5 .degree. C. The 
reaction was quenched with 1 M HCl (50 mL) and extracted with EtOAc and 
water, then brine. After drying (Na.sub.2 SO.sub.4), filtering, and 
evaporation, the product was purified by two silica gel chromatographies, 
initially eluting with EtOAc/hexane, then methanol/chloroform gradients. 
Evaporation of solvent yielded a yellow oil (0.78 g). .sup.1 H NMR(300 
MHz, CDCl.sub.3): 7.90-7.43 (m, 4H), 4.9 g (br, 1H), 4.38 (d, 2H, J=6 Hz), 
3.79 (d, 6H, J=11 Hz), 3.64 (d, 2H, J=23 Hz), 1.47 (s, 9H). 
The chromatographies also yielded many fractions which were a mixture of 
mono- and bis-N-BOC products. These were most readily dealt with by 
complete N-BOC removal by treatment with TFA/CH.sub.2 Cl.sub.2, followed 
by reprotection (di-t-butyl dicarbonate, Et.sub.3 N, EtOAc) to give 
mono-BOC exclusively. Chromatography purification yielded an additional 
2.3 g of the desired product. 
112c) 3-Methoxy-4-(2-methoxy-2-oxo-ethoxy) benzaldehyde 
Vanillin was alkylated with methyl bromoacetate in DMF in the presence of 
K.sub.2 CO.sub.3 in the usual way to give a colorless solid (77%). mp 
91.degree.-93 .degree. C. IR(KBr) cm.sup.-1 1760, 1682. .sup.1 H NMR(300 
MHz, CDCl.sub.3): 9.86 (s, 1H), 7.44-7.40 (m, 2H), 6.86 (d, 1H, J=8 Hz), 
4.79 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H). Anal. Calc'd for C.sub.11 
H.sub.12 O.sub.5 : C, 58.92; H, 5.41; Found: C, 59.02; H, 5.26. 
112d) (E)-Methyl 
4-[3-((3-N-(t-butyloxycarbonyl)amino-methyl))phenyl-3-oxo-1-propenyl]-2-me 
thoxyphenoxyacetate 
Benzaldehyde 112c and .beta.-ketophosphonate 112b were condensed in the 
usual way to give a yellow glassy solid (76%). IR (KBr) cm.sup.-1 3368, 
1760, 1708, 1660. .sup.1 H NMR (300 MHz, CDCl.sub.3): 7.90 (m, 2H ), 7.74 
(d, 1H, J=16 Hz), 7.50-7.46 (m, 2H), 7.36 (d, 1H, J=16 Hz), 7.20-7.17 (m, 
2H), 6.81 (d, 1H, J=8 Hz), 4. 90 (br, 1H), 4.75 (s, 2H), 4.39 (d, 2H, J=6 
Hz), 3.95 (s, 3H), 3.80 (s, 3H), 1.45 (s, 9H). HR-MS: Calc'd. 473.2288, 
Found 473.2291. 
112e) (E)-Methyl 
4-[3-((3-(aminomethyl)phenyl))-3-oxo-1-propenyl]-2-methoxyphenoxyacetate.m 
ultidot.trifluoroacetate 
BOC-amine 122d was deprotected with TFA/CH.sub.2 Cl.sub.2 in the usual way 
to yield a yellow solid (79%). IR(KBr) cm.sup.-1 1756, 1704, 1656. .sup.1 
H NMR(300 MHz, DMSO): 8.26-8.21 (m, 4H), 7.83 (d, 1H, J=16 Hz), 7.76-6.96 
(m, 6H), 4.89 (s, 2H), 4.20-4.14 (m, 2H), 3.89 (s, 3H), 3.71 (s, 3H). 
HR-MS: Calc'd. 356.1498, Found 356.1505. 
112f) 
N,N'-bis-(t-Butyloxycarbonyl)-3,5-dimethyl-1H-pyrazole-1-carboxamidine 
This reagent was prepared according to the method recently reported 
(Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron Letters 1993, 34, 
3389-92) for the des-dimethyl analog, yielding a white solid in 70% over 
two steps. mp 94.degree.-96 .degree. C. IR(KBr) cm.sup.-1 3338, 2338, 
1770, 1710, 1674. .sup.1 H NMR (300 MHz, CDCl.sub.3): 9.03 (s, 1H), 5.95 
(s, 1H), 2.55 (s, 3H), 2.20 (s, 3H), 1.53 (s, 9H), 1.49 (s, 9H). Anal. 
Calc'd for C.sub.16 H.sub.26 N.sub.4 O.sub.4 : C, 56.77; H, 7.76; N, 
16.56; Found: C, 56.81; H, 7.71; N, 16.46. HR-MS: Calc'd. 339.2032, Found 
339.2031. 
112g) (E)-Methyl 
4-[3-((3-N,N'-bis-(t-butyloxycarbonyl)guanidinylmethyl))phenyl-3-oxo-1-pro 
penyl]-2-methoxyphenoxyacetate 
Benzylic amine salt 112e (0.78 g, 1.7 mmol), N,N'-bis-BOC-pyrazole 
carboxamidine 122f (0.51 g, 1.5 mmol), and Et.sub.3 N (0.23 mL, 17 mmol), 
were stirred in THF (5 mL) at room temperature for 44 h. After evaporation 
of solvent, the product was isolated by chromatography on silica gel, 
eluting with 30% to 50% EtOAc in hexane, to yield a yellow solid (0.81 g) 
following solvent evaporation. IR(KBr) cm.sup.-1 3328, 2338, 1760, 1726. 
.sup.1 H NMR(300 MHz, CDCl.sub.3): 11.54 (br, 1H), 8.60 (br, 1H), 7.91 (m, 
2H), 7.74 (d, 1H, J-16 Hz), 7.54-6.81 (m, 6H), 5.95 (s, 1H), 4.75 (s, 2H), 
4 . 72 (d, 2H, J=6 Hz), 3.96 (s, 3H), 3.81 (s, 3H), 1.51 (s, 9H), 1.47 
(s, 9H). MS (NH.sub.3): 598 (base, M+H). 
112h) 
(E)-4-[3-((3-(Quanidinylmethyl)phenyl))-3-oxo-1-propenyl]-2-methoxyphenoxy 
acetic acid.multidot.trifluoroacetate 
Methyl ester 112g (0.20 g, 0.33 mmol) was saponified by stirring with 1 M 
aq. NaOH (0.33 mL, 0.33 mmol) in MeOH (10 mL) for 22 h. Acidification with 
1 M HCl and EtOAc extraction allowed isolation of the carboxylic acid as a 
yellow glassy solid (quant.). HR-MS: Calc'd. 584.2608, Found 584.2600. 
This crude carboxylic acid was deprotected with TFA/CH.sub.2 Cl.sub.2 in 
the usual way to yield a hygroscopic yellow powder (0.11 g). IR(KBr) 
cm.sup.-1 3500-2700, 1738, 1668. HR-MS: Calc'd. 384.1559, Found 384.1567. 
Example 120 
(E)-4-[3-((3-(1-piperazinyl)phenyl)-3-oxo-1-propenyl]-2-methoxyphenoxyaceti 
c acid.multidot.trifluoroacetate 
120a) Methyl 3-((N,N-bis-(2-hydroxyethyl)amino))benzoate 
Ethylene oxide (16 mL, 330 mmol) was added rapidly via a cold syringe to a 
solution of methyl 3-aminobenzoate (5.0g, 33 mmol), glacial acetic acid 
(40 mL), and water (40 mL) with stirring at 0 .degree. C. under nitrogen 
beneath a dry ice/acetone condenser. After 1 h, the cold bath was removed 
and the reaction stirred for 43 h at room temperature. Water was added, 
and the mixture neutralized by adding solid sodium bicarbonate 
portionwise. After a series of EtOAc/H.sub.2 O extractions, the crude 
product was isolated by concentration under reduced pressure. Purification 
by chromatography on silica gel, eluting with 0% to 5% MeOH in EtOAc, and 
evaporation yielded an oil (6.9 g). IR(neat): cm.sup.-1 3340, 1718. .sup.1 
H NMR(300 MHz, CDCl.sub.3): 7.38-6.87 (m, 4H), 3.90-3.85 (m, 7H), 
3.65-3.59 (m, 4H), 3.27 (s, 2H). HR-MS: Calc'd. 240.1236, Found 240.1237. 
120b) Methyl 3-((N,N-bis-(2-chloroethyl)amino))benzoate 
A solution of 120a (6.9 g, 29 mmol) in chloroform (50 mL) was added over 2 
h to POCl.sub.3 (9.9 g) with heating under reflux. After 2.7 h additional 
reflux, the mixture was cooled in an ice bath, and filtered to remove a 
white precipitate. The filtrate was neutralized by extraction with 
saturated aqueous NaHCO.sub.3 and chloroform. The organic phase was dried 
(Na.sub.2 SO.sub.4), filtered, and evaporated to an oil (5.4 g). IR(neat): 
cm.sup.-1 1720. .sup.1 H NMR(300 MHz, CDCl.sub.3): 7.42-6.87 (m, 4H), 
3.90(s, 3H), 3.77 (t,4H, J=7 Hz), 3.64 (t, 4H, J=7 Hz). HR-MS: Calc'd. 
276.0558, Found 276.0553. 
120c) Methyl 3-(4-benzyl-1-piperazinyl)benzoate 
Benzylamine (1.2 mL, 11 mmol), 120b (1.0 g, 3.6 mmol), water (50 mL), and 
acetone (50 mL) were heated at reflux for 28 h, then stirred at room 
temperature an additional 41 h. After evaporation of the acetone, the 
mixture was extracted with EtOAc (2.times.). The organic phase was 
extracted further with water and brine, then dried (Na.sub.2 SO.sub.4), 
filtered and concentrated. The product was purified by chromatography on 
silica gel, eluting with 30% to 50% EtOAc in hexanes, then evaporated to 
yield a yellow oil (0.57 g). IR(neat): cm.sup.-1 1722. .sup.1 H NMR (300 
MHz, CDCl.sub.3): 7.57-7.08 (m, 9H), 3.88 (s, 3H), 3.56 (s, 2H), 3.24 (m, 
4H), 2.61 (m, 4H). HR-MS: Calc'd. 311.1760, Found 311.1764. 
120d) Methyl 3-(1-piperazinyl)benzoate.multidot.p-toluene sulfonic acid 
A mixture of 120c (2.6 g, 8.5 mmol), p-toluene sulfonic acid (1.6 g, 8.5 
mmol), 10% Pd/C (0.52 g) and MeOH (40 mL) were shaken on a Parr 
hydrogenation apparatus at 49 psi of H.sub.2. After TLC indicated complete 
reaction, the catalyst was removed by filtration through a Celite pad, and 
solvent was evaporated to yield a white solid (3.3 g). IR(KBr): cm.sup.-1 
3416, 1724. .sup.1 H NMR(300 MHz, CDCl.sub.3): 8.70 (br, 1H), 7.51-7.28 
(m, 6H), 7.12 (d, 2H, J=8 Hz), 4.10 (br, 1H), 3.85 (s, 3H), 3.41-3.24 (m, 
8H), 2.29 (s, 3H). HR-MS: Calc'd. 221.1290, Found 221.1294. 
120e) Methyl 3-((4-(t-butyloxycarbonyl)-1-piperazinyl)benzoate 
Piperazine salt 120d (3.3 g, 8.1 mmol), Et.sub.3 N (1.2 mL, 8.6 mmol), 
di-t-butyl dicarbonate (1.8 g, 8.2 mmol), EtOAc (40 mL), and MeOH (a few 
mL, to aid solubility) were stirred at room temperature for 6 h. The 
mixture was diluted with EtOAc and extracted with water, 5% aq. 
KHSO.sub.4, saturated NaHCO.sub.3, and brine, then dried (Na.sub.2 
SO.sub.4), filtered and concentrated. A yellow oil (2.6 g) was obtained. 
IR(neat): cm.sup.-1 1722, 1690. .sup.1 H NMR(300 MHz, CDCl.sub.3): 
7.57-7.09 (m, 4H), 3.89 (s, 3H), 3.58 (t, 2H, J=5 Hz), 3.17 (t, 4H, J=5 
Hz), 1.47 (s, 9H). HR-MS: Calc'd. 321.1814, Found 321.1809. 
120f) 
(E)-4-[3-((3-(1-Piperazinyl)phenyl)-3-oxo-1-propenyl]-2-methoxyphenoxyacet 
ic acid.multidot.trifluoroacetate 
Methyl ester 120e was converted to its .beta.-ketophosphonate, coupled with 
aldehyde 23a, and deprotected as usual to yield a solid. IR(KBr): 
cm.sup.-1 3150-2480, 1754, 1660. .sup.1 H NMR (300 MHz, CDCl.sub.3): 13.0 
(br, 1H), 8.8 (br, 1H), 7.79 (d, 1H, J=15 Hz), 7.71-7.30 (m, 7 H), 6.92 
(d, 1H, J=8 Hz), 4.76 (s, 2H), 3.88 (s, 3H), 3.50-3.35 (m, 4H), 3.28-3.22 
(m, 4H). HR-MS: Calc'd. 397.1763, Found 397.1773. 
Example 121 
(E)-4-[[3-[3-((2-(methylamino)ethoxy))-phenyl]-3-oxo-1-propenyl]]-2-methoxy 
phenoxyacetic acid .multidot.trifluoroacetate 
121a) N-t-Butyloxycarbonyl-N-methyl-2-aminoethanol 
A solution of di-t-butyl dicarbonate (10 g, 46 mmol) in EtOH (40 mL) was 
added dropwise over 50 min to a solution of 2-(methylamino)ethanol (4.0 
mL, 50 mmol) in EtOH (40 mL) with stirring in an ice bath. The mixture was 
stirred for 2 h at 0 .degree. C., then 17.5 h at room temperature. After 
evaporation of solvent, the mixture was extracted with EtOAc and water, 
then brine. Drying (MgSO.sub.4), filtration, and evaporation yielded a 
colorless oil (7.4 g). IR (film) cm.sup.-1 3448, 1698. .sup.1 H NMR (300 
MHz, CDCl.sub.3): 3.77-3.71 (m, 2H), 3.40-3.37 (m, 2H), 2.91 (s, 3H), 1.45 
(s, 9H). Anal. Calc'd for C.sub.8 H.sub.17 NO.sub.3 : C, 54.84; H, 9.78; 
N, 7.99; Found: C, 54.58; H, 9.50; N, 7.89. MS(NH.sub.3): 193 (76%, 
M+NH.sub.4), 176 (base, M+H). 
121b) Methyl 3-((2-(N-t-Butyloxycarbonyl-N-methylamino)ethoxy))benzoate 
Methyl 3-hydroxybenzoate (6.4 g, 42 mmol), alcohol 121a (7.4 g, 42 mmol), 
diisopropyl azodicarboxylate (8.3 mL, 42 mmol), and triphenylphosphine 
(11.1 g, 42 mmol) were stirred in dry THF (120 mL) at 0 .degree. C. for 1 
h, then for 18 h at room temperature. After evaporation of solvent, the 
product was isolated by chromatography on silica gel, eluting with 0% to 
30% EtOAc in hexane to yield a clear oil (9.4 g). IR(film) cm.sup.-1 1726, 
1696. .sup.1 H NMR(300 MHz, CDCl.sub.3): 7.64-7.09 (m, 4H), 4.13 (m, 2H), 
3.92 (s, 3H), 3.62 (br, 2H), 2.99 (s, 3H), 1.46 (s, 9H). Anal. Cald'd for 
C.sub.16 H.sub.23 NO.sub.5 : C, 62.11; H, 7.51; N, 4.53; Found: C, 61.67; 
H, 7.43; N, 4.47. HR-MS: Calc'd. 310.1654, Found 310.1650. 
121c) 
(E)-4-[[3-[3-((2-(Methylamino)ethoxy))-phenyl]-3-oxo-1-propenyl]]-2-methox 
yphenoxyacetic acid.multidot.trifluoroacetate 
Methyl ester 121b was converted to its .beta.-ketophosphonate, coupled with 
aldehyde 23a and deprotected in the usual way to yield a yellow solid. 
IR (KBr) cm.sup.-1 3300-2700, 1730, 1658. .sup.1 H NMR (300 MHz, 
CDCl.sub.3): 8.63 (br, 2H), 7.87 (d, 1H, J=8 Hz), 7.81 (d, 1H, J=15 Hz), 
7.71 (d, 1H, J=15 Hz), 7.62-6.92 (m, 6H), 4.76 (s, 2H), 4.33 (t, 2H, J=5 
Hz), 3.88 (s, 3H), 3.56-3.35 (m, 2H), 2.67 (t, 3H, J=5 Hz). HR-MS: Calc'd. 
386.1604, Found 386.1603. 
Example 126 
4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propyl]phenoxyacetic 
acid.multidot.hydrochloride 
126a) 
4-[3-((3-(2-t-Butyloxycarbonylamino)ethoxyphenyl)-3-oxo-1-propyl]phenoxyac 
etic acid 
Enone 1d (0.10 g, 0.23 mmol) and platinum oxide (10 mg) were shaken on a 
Parr hydrogenation apparatus at 10 psi H.sub.2 in a mixture of ethanol (25 
mL) and methanol (10 mL) for 18 h. The catalyst was removed by filtration 
through a Celite pad, and solvent was removed in vacuo to give a gum (0.16 
g, incompletely dried). MS (NH.sub.3): 461 (base, M+NH.sub.4). 
126b) 4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propyl]-phenoxyacetic 
acid.multidot.hydrochloride 
Deprotection as described above for 1e gave an orange-tan solid (88 mg) 
which contained .about.20% of an inseparable impurity. IR(nujol): cm.sup.1 
3400-2600, 1738, 1678. HR-MS: Calc'd 344.1498, Found 344.1515. 
In addition to the synthesis of the compounds specifically described above, 
additional representative examples of compounds of this invention are 
provided below. These compounds were synthesized by the use of synthetic 
routes and procedures as described above, and variations thereof which 
would be known to those skilled in the art of synthetic organic chemistry. 
Ex. 20. (E)-Ethyl 
5-[3-((3-(2-aminoethoxy)-5-ethoxyphenyl))-3-oxo-1-propenyl]-2-(carboxymeth 
oxy)benzoate.multidot.trifluoroacetate. HR-MS: Calc'd 458.1815, Found 
458.1806. 
Ex. 21. 
(E)-4-[3-((3-(2-Aminoethoxy)-5-ethoxyphenyl))-3-oxo-1-propenyl]phenoxyacet 
ic acid.multidot.trifluoroacetate. HR-MS(NH.sub.3): Calc'd 386.1604, Found 
386.1599. 
Ex. 22. 
(E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-ethoxyphenoxyacet 
ic acid .multidot.trifluoroacetate. IR (KBr): cm.sup.-1 3600-2400, 1738, 
1680. MS(NH.sub.3): 386 (base, M+H). 
Ex. 25. (E)-(Carboxymethyl) 
5-[3-((3-(2-aminoethoxy)-phenyl))-3-oxo-1-propenyl]-2-(carboxymethyoxy)ben 
zoate.multidot.trifluoroacetate. .sup.1 H-NMR (300 MHz, d.sub.6 -DMSO): 
8.35 (br s, 1H), 8.05-8.02 (br d, 1H, J=8 Hz), 7.85-7.78 (m, 3H), 7.75 (d, 
1H, J=15 Hz), 7.65 (br s, 1H), 7.56-7.50 (br t, 1H, J=8 Hz ), 7.30-7.27 
(br d, 1H, J=9 Hz), 7.13-7.10 (br d, 1H, J=9 Hz), 4.84 (s, H), 4.71 (s, 
2H), 4.39-4.30 (m, 2H), 3.28-3.24 (m, 2H). IR (KBr): cm.sup.-1 3600-2400, 
1730, 1702, 1658, 1584. 
Ex. 26. 
(E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-nitrophenoxyaceti 
c acid.multidot.trifluoroacetate. MS (NH.sub.3): 387 (base, M+H). mp. 
167.degree.-168.degree. C. 
Ex. 27. (E)-(2-Ethoxy-2-oxoethyl) 
5-[3-((3-(2-amino-ethoxy)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)-ben 
zoate.multidot.trifluoroacetate. HR-MS (NH.sub.3): Calc'd 472.1608, Found 
472.1605. 
Ex. 28. (E)-Benzyl 5-[3-((3-(2-aminoethoxy) 
phenyl))-3-oxo-1-propenyl]-2(carboxymethoxy) 
benzoate.multidot.trifluoroacetate. HR-MS (NH.sub.3): Calc'd 476.1709, 
Found 476.1711. 
Ex. 29. 
(E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]benzene-1,2-bis 
(oxyacetic acid) .multidot.trifluoroacetate. HR-MS (NH.sub.3): Calc'd 
416.1345, Found 416.1335. 
Ex. 30. (E)-Methyl 5-[3-((3-(2-aminoethoxy) 
phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy) 
benzoate.multidot.trifluoroacetate. HR-MS (NH.sub.3): Calc'd 400.1396, 
Found 400.1407 . 
Ex. 43. (E)-(Carboxymethyl) 
5-[3-((2-(benzyloxy)-5-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl]-2-(carbox 
ymethoxy) benzoate.multidot.trifluoroacetate. HR-MS(NH.sub.3): Calc'd 
550.1713, Found 550.1723. 
Ex. 44. (E)-(Carboxymethyl) 
5-((3-((2-(1-prop-2-enyloxy)-5-(2-aminoethoxy)phenyl))-3-oxo-1-propenyl))- 
2-(carboxymethoxy) benzoate.multidot.trifluoroacetate. HR-MS (NH.sub.3): 
Calc'd 500.1557, Found 500.1557. 
Ex. 65. 
(E)-4-[3-((3-(2-Aminoethoxy)phenyl))-3-oxo-1-propenyl]-3-methoxyphenoxyace 
tic acid .multidot.hydrochloride. HR-MS(NH.sub.3): Calc'd 372.1447, Found 
2.1431. 
Ex. 101. (E)-Ethyl 
5-[3-((3-(2-aminopropyl)phenyl))-3-oxo-1-propenyl]-2-(carboxymethoxy)benzo 
ate.multidot.trifluoroacetate. HR-MS (NH.sub.3): Calc'd 412.1760, Found 
412.1765. 
Ex. 211. (E)-4-[3-((3-(2-aminoethoxy) 
phenyl))-1-oxo-prop-2-enyl]-2-methoxyphenoxyacetic 
acid.multidot.trifluoroacetate. MS (NH.sub.3): 372 (base, M+H). 
Example 300 
(+/-)-trans-[[2-methoxy-4-[2-((3-(1-piperazinyl)benzoyl))cyclopropyl]phenox 
y]]acetic acid.multidot.trifluoroacetic acid 
300a) (+/-)-trans-t-Butyl 
[[2-methoxy-4-[2-((3-(4-t-butyloxycarbonyl-1-piperazinyl)benzoyl))cyclopro 
pyl]-phenoxy]]acetate 
Sodium hydride (24 mg, 0.60 mmol) was added to a solution of 
trimethylsulfoxonium iodide (0.13 g, 0.60 mmol) in dry DMSO (1 mL), 
accompanied by gas evolution. After 30 min, the fully protected enone 
(immediate precursor for 120f, 300 mg, 0.54 mmol) was added. After 2h at 
room temperature, the reaction was heated to 60.degree. C. for 100 min. 
After cooling, the reaction was extracted with EtOAc and water, then 
brine, then dried (Na.sub.2 SO.sub.4), filtered, and concentrated. The 
product was purified by silica gel chromatography, eluting with 20% to 30% 
acetone in hexane to provide a yellow glassy solid (109 rag). IR(KBr): 
cm.sup.-1 1752, 1696, 1666. HR-MS: Calc'd 567.3070, Found 567.3075. 
300b) (+/-)-trans-[[2-methoxy-4-[2-((3-(1-piperazinyl) 
benzoyl))cyclopropyl]phenoxy]]acetic acid.multidot.trifluoroacetic acid. 
Cyclopropyl adduct 300a was deprotected with TFA/CH.sub.2 Cl.sub.2 in the 
usual way to provide a pale grey solid. IR(KBr): cm.sup.-1 3200-2500(br), 
1738, 1680. HR-MS: Calc'd 411.1920, Found 411.1925. 
Example 330 
[6-((3-(2-Aminoethoxy)benzoyl))-2-naphthalenyloxy]acetic 
acid.multidot.trifluoroacetic acid 
330a) 6-Bromo-2-(t-butyldimethylsilyloxy) naphthalene 
6-Bromo-2-naphthol (10 g, 44 mmol), imidazole (7.4 g, 110 mmol), and 
t-butyldimethylsilyl chloride (10 g, 66 mmol) were stirred in DMF (50 mL) 
at room temperature overnight. TLC analysis indicated incomplete reaction, 
so additional imidazole (0.6 g) and silyl chloride (1.3 g) were added, and 
stirring continued 1 day. After evaporation of DMF, the mixture was 
extracted with EtOAc and 5% aqueous KHSO.sub.4, dried (Na.sub.2 SO.sub.4), 
and evaporated. The crude product was purified by silica gel 
chromatography, eluting with hexane, to yield a colorless solid (11 g). mp 
62.degree.-63.degree. C. .sup.1 H NMR (300 MHz, CDCl.sub.3): 7.90 (d, 1H, 
J=l Hz), 7.62 (d, 1H, J=9 Hz), 7.55 (d, 1H, J=9 Hz), 7.46 (dd, 1H, J=9, 2 
Hz), 7.14 (d, 1H, J=2 Hz), 7.08 (dd, 1H, J=9,2 Hz), 1.00 (s, 9H), 0.23 (s, 
6H). MS(CH4): 365 (20%, M+C.sub.2 H.sub.5, 1 Br isotope pattern), 337 
(base, M+H, 1 Br isotope pattern). 
330b) 3-(20t-Butyloxycarbonylaminoethoxy)benzaldehyde 
Diisopropylazodicarboxylate (2.0 mL, 10 mmol) was added to a solution of 
3-hydroxybenzaldehyde (1.23 g, 10 mmol), 2-(t-butyloxycarbonylamino) 
ethanol (1.6 g, 10 mmol), and triphenylphosphine (2.7 g, 10 mmol) with 
stirring in dry THF (50 mL) in an ice bath. After allowing the reaction 
mixture to warm to room temperature overnight, the solvent was evaporated 
under vacuum. The mixture was diluted with EtOAc (300 mL) and extracted 
with 1 M NaOH (20 mL), water (2.times.20 mL), and brine (10 mL). After 
drying (MgSO.sub.4), and evaporation, the product was purified by 
chromatography on silica gel, eluting with 0% to 50 % EtOAc in hexane. 
Evaporation of solvent yielded a pale yellow viscous oil (1.6 g), which 
was only about 80% pure. .sup.1 H NMR(300 MHz, CDCl.sub.3): major 
component 9.97 (s, 1H), 7.48-7.13 (m, 4H), 4.97 (br, 1H), 4.09-4.05 (m, 
2H), 3.58-3.53 (m, 2H), 1.45 (s, 9H). IR (neat): cm.sup.-1 3353 (s, br), 
1694 (s). MS(NH.sub.3): 283 (base, M+NH.sub.4). 
330c) 
1-[3-((2-(t-Butyloxycarbonylamino)ethoxy)phenyl]-1-((6-(t-butyldimethylsil 
yloxy)-2-naphthalenyl))methanol 
n-Butyllithium (1.6 M in hexane, 15 mL, 24 mmol) was added dropwise to a 
-78.degree. C. solution of naphthyl bromide 330a (8.0 g, 24 mmol) in dry 
THF (60 mL). After 0.5 h, a solution of aldehyde 330b (3.2 g, 12 mmol) in 
dry THF (40 mL) was added. The reaction mixture was maintained at 
-78.degree. for 5h, then allowed to warm to room temperature overnight. 
After evaporation of solvent, the mixture was extracted with EtOAc and 5% 
aq. KHSO.sub.4, and dried (Na.sub.2 SO.sub.4). After concentration, the 
product was purified by chromatography on silica gel, eluting with 0% to 
50% EtOAc in hexane. Solvent removal yielded a yellow oil (2.0 g). IR(thin 
film): cm.sup.-1 3420, 1696. MS(NH.sub.3): 541 (base, M+NH4). 
330d) 
6-[3-((2-(t-Butyloxycarbonylamino)ethoxy))benzoyl]-2-(t-butyldimethylsilyl 
oxy)naphthalene 
Alcohol 330c (2.0 g) and MnO.sub.2 were stirred in CH.sub.2 Cl.sub.2 (50 
mL) under N.sub.2 at room temperature for 3h. More MnO.sub.2 (2.times.2.0 
g) was added in portions over the next 24 h and stirring continued until 
TLC analysis indicated complete reaction. After solvent removal, the 
product was purified by chromatography on silica gel, eluting with 0% to 
30% EtOAc in hexane. Evaporation of solvents yielded a clear glassy solid 
(1.07 g). MS(NH.sub.3): 539 (base, M+NH.sub.4). Anal. Calc'd for C.sub.30 
H.sub.39 NO.sub.5 Si: C, 69.06; H, 7.53; N, 2.68; Si, 5.38; Found: C, 
68.76; H, 7.45; N, 2.69; Si, 5.31. 
330e) 
6-[3-((2-(t-Butyloxycarbonylamino)ethoxy))-benzoyl]-2-hydroxy-naphthalene 
Silyl ether 330d (1.0 g, 1.9 mmol) and tetrabutylammonium fluoride (1 M in 
THF, 1.9 mL, 1.9 mmol) were stirred in THF (40 mL) at room temperature 
under N.sub.2 for 2h. After solvent evaporation, the mixture was extracted 
with EtOAc and 5% aq. KHSO.sub.4, then water, finally brine. Concentration 
and chromatography on silica gel, eluting with 0% to 40% EtOAc in hexane 
yielded, after drying, a colorless foam (0.70 g). IR(KBr): cm.sup.-1 3334, 
1686. MS (NH.sub.3): 425 (M+NH.sub.4), 402 (M+H). 330f) t-Butyl 
[[6-[3-((2-(t-Butyloxycarbonylamino)-ethoxy))-benzoyl]-2-naphthalenyloxy]] 
acetate 
2-Hydroxynaphthalene 330e (0.60 g, 1.5 mmol) was alkylated with 
t-butylbromoacetate (0.24 mL, 1.5 mmol) in the presence of K.sub.2 
CO.sub.3 (0.20 g, 1.5 mmol) in DMF (7 mL) in the usual way to yield a 
colorless solid (0.64 g) after silica gel chromatography. IR(KBr): 
cm.sup.-1 3340, 1746, 1684. .sup.1 H NMR(300 MHz, CDCl.sub.3): 8.21 (s, 
1H), 7.94-7.10 (m, 9H), 5.0 (br, 1H), 4.68 (s, 2H), 4.09 (t, 2H, J=7 Hz), 
3.56-3.52 (m, 2H), 1.52 (s, 9H), 1.44 (2, 9H). MS (NH.sub.3): 539 (base, 
M+NH4), 522 (25%, M+H). 
330g) [6-((3-(2-Aminoethoxy)benzoyl))-2-naphthalenyloxy]acetic 
acid.multidot.trifluoroacetic acid. 
N-BOC-t-butyl ester 330f (0.59 g) and trifluoroacetic acid (1 mL) were 
stirred in CH.sub.2 Cl.sub.2 in the usual way to give the fully 
deprotected salt (0.48 g) as an off-white solid. .sup.1 H NMR(300 MHz, d-6 
DMSO): 8.27-7.25 (m, 13H), 4.84 (s, 2H), 4.22 (t, 2H, J=7 Hz), 3.24 (br, 
2H). MS(NH.sub.3): 383 (M+NH.sub.4), 366 (M+H). 
Ex. 315. 
(+/-)-trans-[[2-methoxy-4-[2-((3-(2-aminoethoxy)benzoyl))cyclopropyl]pheno 
xy]]acetic acid.multidot.trifluoroacetic acid MS (NH.sub.3): 404 (5% 
M+NH.sub.4), 386 (base, M+H). 
In the Tables below, HN(CH.sub.2 CH.sub.2).sub.2 .sup.N represents the 
group 
##STR31## 
Utility 
The compounds of this invention possess antiplatelet efficacy, as evidenced 
by their activity in standard platelet aggregation assays or platelet 
fibrinogen binding assays, as described below. A compound is considered to 
be active in these assays if it has an IC.sub.50 value of less than about 
1 mM. Platelet aggregation and fibrinogen binding assays which may be used 
to demonstrate the antiplatelet activity of the compounds of the invention 
are described below. 
Platelet Aggregation Assay: Venous blood was obtained from the arm of a 
healthy human donor who was drug-free and aspirin-free for at least two 
weeks prior to blood collection. Blood was collected into 10 mL citrated 
Vacutainer tubes. The blood was centrifuged for 15 minutes at 150.times.g 
at room temperature, and platelet-rich plasma (PRP) was removed. The 
remaining blood was centrifuged for 15 minutes at 1500.times.g at room 
temperature, and platelet-poor plasma (PPP) was removed. Samples were 
assayed on a aggregometer (PAP-4 Platelet Aggregation Profiler), using PPP 
as the blank (100% transmittance). 200 .mu.L of PRP was added to each 
micro test tube, and transmittance was set to 0%. 20 .mu.L of various 
agonists (ADP, collagen, arachidonate, epinephrine, thrombin) were added 
to each tube, and the aggregation profiles were plotted (% transmittance 
versus time). The results are expressed as % inhibition of agonist-induced 
platelet aggregation. For the IC.sub.50 evaluation, the test compounds 
were added at various concentrations prior to the activation of the 
platelets. 
Purified GPIIb/IIIa-Fibrinogen Binding ELISA 
The following reagents are used in the GPIIb/IIIa-fibrinogen binding ELISA: 
purified GPIIb/IIIa (148.8 .mu.g/mL); 
biotinylated fibrinogen (.about.1 mg/mL or 3000 nM); 
anti-biotin alkaline phosphatase conjugate (Sigma no. A7418); 
flat-bottom, high binding, 96-well plates (Costar Cat. no. 3590); 
phosphatase substrate (Sigma 104) (40 mg capsules); 
bovine serum albumin (BSA) (Sigma no. A3294); 
Alkaline Phosphatase buffer--0.1 M glycine-HCl, 1 mM MgCl.sub.2 
.multidot.6H.sub.2 O, 1 mM ZnCl.sub.2, pH 10.4; 
Binding buffer--20 mM Tris-HCl, 150 mM NaCl, 1 mM CaCl.sub.2 
.multidot.2H.sub.2 O, 0.02% NaN.sub.3, pH 7.0; 
Buffer A--50 mM Tris-HCl, 100 mM NaCl, 2 mM CaCl.sub.2 .multidot.2H.sub.2 
O, 0.02% NaN.sub.3, pH 7.4; 
Buffer A+3.5% BSA (Blocking buffer); 
Buffer A+0.1% BSA (Dilution buffer); 
2N NaOH. 
The following method steps are used in the GPIIb/IIIa-fibrinogen binding 
ELISA: 
Coat plates with GPIIb/IIIa in Binding buffer (125 ng/100 .mu.L/well) 
overnight at 4 .degree. C. (Leave first column uncoated for non-specific 
binding). Cover and freeze plates at -70 .degree. C./ until used. Thaw 
plate 1 hour at room temperature or overnight at 4 .degree. C. Discard 
coating solution and wash once with 200 .mu.L Binding buffer per well. 
Block plate 2 hours at room temperature on shaker with 200 .mu.l Buffer 
A+3.5% BSA (Blocking buffer) per well. Discard Blocking buffer and wash 
once with 200 .mu.L Buffer A+0.1% BSA (Dilution buffer) per well. Piper 11 
.mu.L of test compound (10.times. the concentration to be tested in 
Dilution buffer) into duplicate wells. Pipet 11 .mu.l Dilution buffer into 
non-specific and total binding wells. Add 100 .mu.L Biotinylated 
fibrinogen (1/133 in Dilution buffer, final concentration=20 nM) to each 
well. Incubate plates for 3 hours at room temperature on a plate shaker. 
Discard assay solution and wash twice with 300 .mu.L Binding buffer per 
well. Add 100 .mu.L Anti-biotin alkaline phosphatase conjugate (1/1500 in 
Dilution buffer) to each well. Incubate plates for 1 hour at room 
temperature on plate shaker. Discard conjugate and wash twice with 300 51 
Binding buffer per well. Add 100 .mu.L Phosphatase substrate (1.5 mg/ml in 
Alkaline phosphatase buffer) to each well. Incubate plate at room 
temperature on shaker until color develops. Stop color development by 
adding 25 .mu.L 2N NaOH per well. Read plate at 405 nm. Blank against 
non-specific binding (NSB) well. % Inhibition is calculated as 
100 -(Test Compound Abs/Total Abs).times.100. 
Platelet-Fibrinogen Binding Assay: Binding of .sup.125 I-fibrinogen to 
platelets was performed as described by Bennett et al. (1983) Proc. Natl. 
Acad. Sci. USA 80: 2417-2422, with some modifications as described below. 
Human PRP (h-PRP) was applied to a Sepharose column for the purification 
of platelet fractions. Aliquots of platelets (5.times.108 cells) along 
with 1 mM calcium chloride were added to removable 96 well plates prior to 
the activation of the human gel purified platelets (h-GPP). Activation of 
the human gel purified platelets was achieved using ADP, collagen, 
arachidonate, epinephrine, and/or thrombin in the presence of the ligand, 
.sup.125 I-fibrinogen. The .sup.125 I-fibrinogen bound to the activated 
platelets was separated from the free form by centrifugation and then 
counted on a gamma counter. For an IC.sub.50 evaluation, the test 
compounds were added at various concentrations prior to the activation of 
the platelets. 
The compounds of Formula I of the present invention may also possess 
thrombolytic efficacy, that is, they are capable of lysing (breaking up) 
already formed platelet-rich fibrin blood clots, and thus are useful in 
treating a thrombus formation, as evidenced by their activity in the tests 
described below. Preferred compounds of the present invention for use in 
thrombolysis include those compounds having an IC.sub.50 value (that is, 
the molar concentration of the compound capable of achieving 50% clot 
lysis) of less than about 1 mM, more preferably an IC.sub.50 value of less 
than about 0.1 mM. 
Thrombolytic Assay: Venous blood was obtained from the arm of a healthy 
human donor who was drug-free and aspirin free for at least two weeks 
prior to blood collection, and placed into 10 ml citrated Vacutainer 
tubes. The blood was centrifuged for 15 minutes at 1500.times.g at room 
temperature, and platelet rich plasma (PRP) was removed. To the PRP was 
then added 1.times.10.sup.-1 M of the agonist ADP, epinephrine, collagen, 
arachidonate, serotonin or thrombin, or a mixture thereof, and the PRP 
incubated for 30 minutes. The PRP was centrifuged for 12 minutes at 
2500.times.g at room temperature. The supernatant was then poured off, and 
the platelets remaining in the test tube were resuspended in platelet poor 
plasma (PPP), which served as a plasminogen source. The suspension was 
then assayed on a Coulter Counter (Coulter Electronics, Inc., Hialeah, 
Fla.), to determine the platelet count at the zero time point. After 
obtaining the zero time point, test compounds were added at various 
concentrations. Test samples were taken at various time points and the 
platelets were counted using the Coulter Counter. To determine the percent 
of lysis, the platelet count at a time point subsequent to the addition of 
the test compound was subtracted from the platelet count at the zero time 
point, and the resulting number divided by the platelet count at the zero 
time point. Multiplying this result by 100 yielded the percentage of clot 
lysis achieved by the test compound. For the IC.sub.50 evaluation, the 
test compounds were added at various concentrations, and the percentage of 
lysis caused by the test compounds was calculated. 
The compounds of Formula I of the present invention are also useful for 
administration in combination with anti-coagulant agents such as warfarin 
or heparin, or antiplatelet agents such as aspirin, piroxicam or 
ticlopidine, or thrombin inhibitors such as boropeptides, hirudin or 
argatroban, or thrombolytic agents such as tissue plasminogen activator, 
anistreplase, urokinase or streptokinase, or combinations thereof. 
Table A below sets forth the biological activity of representative 
compounds of the present invention. 
TABLE A 
______________________________________ 
Platelet Aggregation Assay 
Example No. IC.sub.50 
______________________________________ 
1 ++ 
2 ++ 
3 +++ 
20 ++ 
21 ++ 
22 +++ 
23 +++ 
24 ++ 
25 +++ 
26 +++ 
27 + 
28 + 
29 ++ 
30 ++ 
43 +++ 
44 +++ 
65 ++ 
75a + 
75b &gt;100 
75c + 
76 + 
91 + 
93 &gt;100 (21% inhibition at 100 .mu.M) 
101 ++ 
112 ++ 
120 +++ 
121 ++ 
125a &gt;100 
126 + 
211 &gt;100 
240 &gt;100 
241 &gt;100 
242 &gt;100 
243 &gt;100 
244 &gt;100 
245 &gt;100 (19% inhibition at 100 .mu.M) 
246 &gt;100 
247 &gt;100 
248 &gt;100 (13% inhibition at 100 .mu.M) 
249 &gt;100 (20% inhibition at 100 .mu.M) 
250 &gt;100 
251 &gt;100 (18% inhibition at 100 .mu.M) 
252 &gt;100 (38% inhibition at 100 .mu.M) 
______________________________________ 
In Table A the biological activity of the compounds is indicated as the 
IC.sub.50 value in the platelet aggregation assay described above. The 
IC.sub.50 values are expressed as: +++=IC.sub.50 of &lt;10 .mu.M; 
++=IC.sub.50 value of 10 .mu.M to 50 .mu.M; +=IC.sub.50 of 51-100 .mu.M. 
As used herein ".mu.M" means micromolar. 
Dosage and Formulation 
The compounds of the present invention can be administered in such oral 
dosage forms as tablets, capsules (each of which includes sustained 
release or timed release formulations), pills, powders, granules, elixirs, 
tinctures, suspensions, syrups, and emulsions. Likewise, they may also be 
administered in intravenous (bolus or infusion), intraperitoneal, 
subcutaneous, or intramuscular form, all using dosage forms well known to 
those of ordinary skill in the pharmaceutical arts. An effective but 
non-toxic amount of the compound desired can be employed as an 
anti-aggregation agent. 
The compounds of this invention can be administered by any means that 
produces contact of the active agent with the agent's site of action, 
glycoprotein IIb/IIIa (GPIIb/IIIa), in the body of a mammal. They can be 
administered by any conventional means available for use in conjunction 
with pharmaceuticals, either as individual therapeutic agents or in a 
combination of therapeutic agents, such as a second antiplatelet agent 
such as aspirin or ticlopidine which are agonist-specific. They can be 
administered alone, but generally administered with a pharmaceutical 
carrier selected on the basis of the chosen route of administration and 
standard pharmaceutical practice. 
The dosage regimen for the compounds of the present invention will, of 
course, vary depending upon known factors, such as the pharmacodynamic 
characteristics of the particular agent and its mode and route of 
administration; the species, age, sex, health, medical condition, and 
weight of the recipient; the nature and extent of the symptoms; the kind 
of concurrent treatment; the frequency of treatment; the route of 
administration, the renal and hepatic function of the patient, and the 
effect desired. An ordinarily skilled physician or veterinarian can 
readily determine and prescribe the effective amount of the drug required 
to prevent, counter, or arrest the progress of the condition. 
By way of general guidance, the daily oral dosage of each active 
ingredient, when used for the indicated effects, will range between about 
0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 
mg/kg of body weight per day, and most preferably between about 1.0 to 20 
mg/kg/day. Intravenously, the most preferred doses will range from about 1 
to about 10 mg/kg/minute during a constant rate infusion. Advantageously, 
compounds of the present invention may be administered in a single daily 
dose, or the total daily dosage may be administered in divided doses of 
two, three, or four times daily. 
The compounds for the present invention can be administered in intranasal 
form via topical use of suitable intranasal vehicles, or via transdermal 
routes, using those forms of transdermal skin patches wall known to those 
of ordinary skill in that art. To be administered in the form of a 
transdermal delivery system, the dosage administration will, of course, be 
continuous rather than intermittant throughout the dosage regimen. 
In the methods of the present invention, the compounds herein described in 
detail can form the active ingredient, and are typically administered in 
admixture with suitable pharmaceutical diluents, excipients, or carriers 
(collectively referred to herein as carrier materials) suitably selected 
with respect to the intended form of administration, that is, oral 
tablets, capsules, elixirs, syrups and the like, and consistent with 
conventional pharmaceutical practices. 
For instance, for oral administration in the form of a tablet or capsule, 
the active drug component can be combined with an oral, non-toxic, 
pharmaceutically acceptable, inert carrier such as lactose, starch, 
sucrose, glucose, methyl callulose, magnesium stearate, dicalcium 
phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral 
administration in liquid form, the oral drug components can be combined 
with any oral, non-toxic, pharmaceutically acceptable inert carrier such 
as ethanol, glycerol, water, and the like. Moreover, when desired or 
necessary, suitable binders, lubricants, disintegrating agents, and 
coloring agents can also be incorporated into the mixture. Suitable 
binders include starch, gelatin, natural sugars such as glucose or 
beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, 
tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene 
glycol, waxes, and the like. Lubricants used in these dosage forms include 
sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, 
sodium acetate, sodium chloride, and the like. Disintegrators include, 
without limitation, starch, methyl cellulose, agar, bentonire, xanthan 
gum, and the like. 
The compounds of the present invention can also be administered in the form 
of liposome delivery systems, such as small unilamellar vesicles, large 
unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed 
from a variety of phospholipids, such as cholesterol, stearylamine, or 
phosphatidylcholines. 
Compounds of the present invention may also be coupled with soluble 
polymers as targetable drug carriers. Such polymers can include 
polyvinylpyrrolidone, pyran copolymer, 
polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, 
or polyethyleneoxidepolylysine substituted with palmitoyl residues. 
Furthermore, the compounds of the present invention may be coupled to a 
class of biodegradable polymers useful in achieving controlled release of 
a drug, for example, polylactic acid, polyglycolic acid, copolymers of 
polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy 
butyric acid, polyorthoesters, polyacetals, polydihydropyrans, 
polycyanoacylates, and crosslinked or amphipathic block copolymers of 
hydrogels. 
Dosage forms (pharmaceutical compositions) suitable for administration may 
contain from about 1 milligram to about 100 milligrams of active 
ingredient per dosage unit. In these pharmaceutical compositions the 
active ingredient will ordinarily be present in an amount of about 0.5-95% 
by weight based on the total weight of the composition. 
The active ingredient can be administered orally in solid dosage forms, 
such as capsules, tablets, and powders, or in liquid dosage forms, such as 
elixirs, syrups, and suspensions. It can also be administered 
parenterally, in sterile liquid dosage forms. 
Gelatin capsules may contain the active ingredient and powdered carriers, 
such as lactose, starch, cellulose derivatives, magnesium stearate, 
stearic acid, and the like. Similar diluents can be used to make 
compressed tablets. Both tablets and capsules can be manufactured as 
sustained release products to provide for continuous release of medication 
over a period of hours. Compressed tablets can be sugar coated or film 
coated to mask any unpleasant taste and protect the tablet from the 
atmosphere, or enteric coated for selective disintegration in the 
gastrointestinal tract. 
Liquid dosage forms for oral administration can contain coloring and 
flavoring to increase patient acceptance. 
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and 
related sugar solutions and glycols such as propylene glycol or 
polyethylene glycols are suitable carriers for parenteral solutions. 
Solutions for parenteral administration preferably contain a water soluble 
salt of the active ingredient, suitable stabilizing agents, and if 
necessary, buffer substances. Antioxidizing agents such as sodium 
bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are 
suitable stabilizing agents. Also used are citric acid and its salts and 
sodium EDTA. In addition, parenteral solutions can contain preservatives, 
such as benzalkonium chloride, methyl- or propyl-paraben, and 
chlorobutanol. 
Suitable pharmaceutical carriers are described in Remington's 
Pharmaceutical Sciences, Mack Publishing Company, a standard reference 
text in this field. 
Useful pharmaceutical dosage-forms for administration of the compounds of 
this invention can be illustrated as follows: 
Capsules 
A large number of unit capsules are prepared by filling standard two-piece 
hard gelatin capsules each with 100 milligrams of powdered active 
ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 
milligrams magnesium stearate. 
Soft Gelatin Capsules 
A mixture of active ingredient in a digestable oil such as soybean oil, 
cottonseed oil or olive oil is prepared and injected by means of a 
positive displacement pump into gelatin to form soft gelatin capsules 
containing 100 milligrams of the active ingredient. The capsules are 
washed and dried. 
Tablets 
A large number of tablets are prepared by conventional procedures so that 
the dosage unit was 100 milligrams of active ingredient, 0.2 milligrams of 
colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 
milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 
milligrams of lactose. Appropriate coatings may be applied to increase 
palatability or delay absorption. 
Injectable 
A parenteral composition suitable for administration by injection is 
prepared by stirring 1.5% by weight of active ingredient in 10% by volume 
propylene glycol and water. The solution is made isotonic with sodium 
chloride and sterilized. 
Suspension: 
An aqueous suspension is prepared for oral administration so that each 5 mL 
contain 100 mg of finely divided active ingredient, 200 mg of sodium 
carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol 
solution, U.S.P., and 0.025 mL of vanillin. 
The compounds of the present invention may be administered in combination 
with a second therapeutic agent selected from: an anti-coagulant agent 
such as warfarin or heparin; an anti-platelet agent such as aspirin, 
piroxicam or ticlopidine; a thrombin inhibitor such as a boropeptide 
thrombin inhibitor, or hirudin; or a thrombolytic agent such as 
plasminogen activators, such as tissue plasminogen activator, 
anistreplase, urokinase or streptokinase. The compound of Formula I and 
such second therapeutic agent can be administered separately or as a 
physical combination in a single dosage unit, in any dosage form and by 
various routes of administration, as described above. 
The compound of Formula I may be formulated together with the second 
therapeutic agent in a single dosage unit (that is, combined together in 
one capsule, tablet, powder, or liquid, etc.). When the compound of 
Formula I and the second therapeutic agent are not formulated together in 
a single dosage unit, the compound of Formula I and the second therapeutic 
agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, 
and/or thrombolytic agent) may be administered essentially at the same 
time, or in any order; for example the compound of Formula I may be 
administered first, followed by administration of the second agent 
(anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or 
thrombolytic agent). When not administered at the same time, preferably 
the administration of the compound of Formula and the second therapeutic 
agent occurs less than about one hour apart, more preferably less than 
about 5 to 30 minutes apart. 
Preferably the route of administration of the compound of Formula I is 
oral. Although it is preferable that the compound of Formula I and the 
second therapeutic agent (anti-coagulant agent, anti-platelet agent, 
thrombin inhibitor, and/or thrombolytic agent) are both administered by 
the same route (that is, for example, both orally), if desired, they may 
each be administered by different routes and in different dosage forms 
(that is, for example, one component of the combination product may be 
administered orally, and another component may be administered 
intravenously). 
The dosage of the compound of Formula I when administered alone or in 
combination with a second therapeutic agent may vary depending upon 
various factors such as the pharmacodynamic characteristics of the 
particular agent and its mode and route of administration, the age, health 
and weight of the recipient, the nature and extent of the symptoms, the 
kind of concurrent treatment, the frequency of treatment, and the effect 
desired, as described above. 
Although the proper dosage of the compound of Formula I when administered 
in combination with the second therapeutic agent will be readily 
ascertainable by a medical practitioner skilled in the art, once armed 
with the present disclosure, by way of general guidance, where the 
compounds of this invention are combined with anti-coagulant agents, for 
example, a daily dosage may be about 0.1 to 100 milligrams of the compound 
of Formula I and about 1 to 7.5 milligrams of the anti-coagulant, per 
kilogram of patient body weight. For a tablet dosage form, the novel 
compounds of this invention generally may be present in an amount of about 
5 to 10 milligrams per dosage unit, and the anti-coagulant in an amount of 
about 1 to 5 milligrams per dosage unit. 
Where the compounds of Formula I are administered in combination with a 
second anti-platelet agent, by way of general guidance, typically a daily 
dosage may be about 0.01 to 25 milligrams of the compound of Formula I and 
about 50 to 150 milligrams of the additional anti-platelet agent, 
preferably about 0.1 to 1 milligrams of the compound of Formula I and 
about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient 
body weight. 
Further, by way of general guidance, where the compounds of Formula I are 
adminstered in combination with thrombolytic agent, typically a daily 
dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per 
kilogram of patient body weight and, in the case of the thrombolytic 
agents, the usual dosage of the thrombolyic agent when administered alone 
may be reduced by about 70-80% when administered with a compound of 
Formula I. 
Where two or more of the foregoing second therapeutic agents are 
administered with the compound of Formula I, generally the amount of each 
component in a typical daily dosage and typical dosage form may be reduced 
relative to the usual dosage of the agent when administered alone, in view 
of the additive or synergistic effect of the therapeutic agents when 
administered in combination. 
Particularly when provided as a single dosage unit, the potential exists 
for a chemical interaction between the combined active ingredients. For 
this reason, when the compound of Formula I and a second therapeutic agent 
are combined in a single dosage unit they are formulated such that 
although the active ingredients are combined in a single dosage unit, the 
physical contact between the active ingredients is minimized (that is, 
reduced). For example, one active ingredient may be enteric coated. By 
enteric coating one of the active ingredients, it is possible not only to 
minimize the contact between the combined active ingredients, but also, it 
is possible to control the release of one of these components in the 
gastrointestinal tract such that one of these components is not released 
in the stomach but rather is released in the intestines. One of the active 
ingredients may also be coated with a sustained-release material which 
effects a sustained-release throughout the gastrointestinal tract and also 
serves to minimize physical contact between the combined active 
ingredients. Furthermore, the sustained-released component can be 
additionally enteric coated such that the release of this component occurs 
only in the intestine. Still another approach would involve the 
formulation of a combination product in which the one component is coated 
with a sustained and/or enteric release polymer, and the other component 
is also coated with a polymer such as a low viscosity grade of 
hydroxypropyl methylcellulose (HPMC) or other appropriate materials as 
known in the art, in order to further separate the active components. The 
polymer coating serves to form an additional barrier to interaction with 
the other component. 
These as well as other ways of minimizing contact between the components of 
combination products of the present invention, whether administered in a 
single dosage form or administered in separate forms but at the same time 
by the same manner, will be readily apparent to those skilled in the art, 
once armed with the present disclosure. 
The present invention also includes pharmaceutical kits useful, for 
example, in the inhibition of platelet aggregation, the treatment of blood 
clots, and/or the treatment of thromboembolic disorders, which comprise 
one or more containers containing a pharmaceutical composition comprising 
a therapeutically effective amount of a compound of Formula I. Such kits 
may further include, if desired, one or more of various conventional 
pharmaceutical kit components, such as, for example, containers with one 
or more pharmaceutically acceptable carriers, additional containers, etc., 
as will be readily apparent to those skilled in the art. Instructions, 
either as inserts or as labels, indicating quantities of the components to 
be administered, guidelines for administration, and/or guidelines for 
mixing the components, may also be included in the kit. 
In the present disclosure it should be understood that the specified 
materials and conditions are important in practicing the invention but 
that unspecified materials and conditions are not excluded so long as they 
do not prevent the benefits of the invention from being realized. 
The Tables below set forth representative compounds of the invention. 
TABLE 1 
__________________________________________________________________________ 
##STR32## 
Ex. 
No. 
R.sup.1 R.sup.2 R.sup.3 R.sup.4 
__________________________________________________________________________ 
1 H H H 6'-CO.sub.2 Et 
2 H H H 6'-CO.sub.2 Et 
3 H 6-OCH.sub.2 CHCH.sub.2 
H 6'-CO.sub.2 Et 
4 H 6-OCH.sub.2 Ph 
H 6'-CO.sub.2 Et 
5 H 6-OCH.sub.2 CH.sub.2 (i-Pr) 
H 6'-CO.sub.2 Et 
6 H 6-CH.sub.2 CH.sub.2 CH.sub.3 
H 6' -CO.sub.2 Et 
7 H 6-CO.sub.2 Me 
H 6'-CO.sub.2 Et 
8 H 6-Br H 6'-CO.sub.2 Et 
9 H 6-OCH.sub.2 CHCH.sub.2 
3'OMe 6'-CO.sub.2 Et 
10 H 6-OCH.sub.2 Ph 
3'OMe 6'-CO.sub.2 Et 
11 H 6-OCH.sub.2 CH.sub.2 (i-Pr) 
3'OMe 6'-CO.sub.2 Et 
12 H 6-CH.sub.2 CH.sub.3 
3'OMe 6'-CO.sub.2 Et 
13 H 6-OCH.sub.2 CHCH.sub.2 
5'OMe 6'-CO.sub.2 Et 
14 H 6-OCH.sub.2 Ph 
5'OMe 6'-CO.sub.2 Et 
15 H 6-OCH.sub.2 CH.sub.2 (i-Pr) 
5'OMe 6'-CO.sub.2 Et 
16 5-CH.sub.2 CH.sub.2 CH.sub.3 
H H 6'-CO.sub.2 Et 
17 5-Br H H 6'-CO.sub.2 Et 
18 5-Br 6-OCH.sub.2 CHCH.sub.2 
H 6'-CO.sub.2 Et 
19 5-OCH.sub.2 CHCH.sub.2 
H H 6'-CO.sub.2 Et 
20 5-OEt H H 6'-CO.sub.2 Et 
21 5-OEt H H H 
22 H H H 6'OEt 
23 H H H 6'-OMe 
24 H H H 6'-CO.sub.2 -n-Bu 
25 H H H 6'-CO.sub.2 CH.sub.2 CO.sub.2 H 
26 H H H 6'-NO.sub.2 
27 H H H 6'-CO.sub.2 CH.sub.2 CO.sub.2 Et 
28 H H H 6'-CO.sub.2 CH.sub.2 Ph 
29 H H H 6'OCH.sub.2 CO.sub.2 H 
30 H H H 6'-CO.sub.2 Me 
31 H H H 6'-F 
32 H H H 6'-Cl 
33 H H H 6'-Br 
34 H H H 6'-I 
35 H H H 6'-CH.sub.2 CH.sub.3 
36 H H 2'-OMe 6'-CO.sub.2 Me 
37 H H 5'OMe 6'-CO.sub.2 Me 
38 H H 2'CO.sub.2 Me 
6'-CO.sub.2 Me 
39 H H 3'-OMe 6'-CO.sub.2 Me 
40 H 6-OCH.sub.2 CHCH.sub.2 
H 6'-CO.sub.2 Me 
41 H 6-OCH.sub.2 Ph 
H 6'-CO.sub.2 Me 
42 5-OEt H H 6'-CO.sub.2 Me 
43 H 6-OCH.sub.2 Ph 
H 6'-CO.sub.2 CH.sub.2 CO.sub.2 H 
44 H 6-OCH.sub.2 CHCH.sub.2 
H 6'-CO.sub.2 CH.sub.2 CO.sub.2 H 
45 H H H 6'-CO.sub.2 CH.sub.2 CO.sub.2 H 
46 H 6-OCH.sub.2 CHCH.sub.2 
H 6'-OMe 
47 H 6-OCH.sub.2 Ph 
H 6'-OMe 
48 H 6-OCH.sub.2 CH.sub.2 (i-Pr) 
H 6'-OMe 
49 5-OEt H H 6'-OMe 
50 5-Br 6-OCH.sub.2 CHCH.sub.2 
H 6'-OMe 
51 H 6-OCH.sub.2 CHCH.sub.2 
H 6'-NO.sub.2 
52 H 6-OCH.sub.2 Ph 
H 6'-NO.sub.2 
53 H H H 6'-NO.sub.2 
54 5-OEt H H 6'-NO.sub.2 
55 5-Br H H 6'-NO.sub.2 
56 5-OCH.sub.2 CHCH.sub.2 
H H 6'-NO.sub.2 
57 5-CH.sub.2 CH.sub.2 CH.sub.3 
H H 6'-NO.sub.2 
58 5-Br 6-OCH.sub.2 CHCH.sub.2 
H 6'-NO.sub.2 
59 H H 5'CO.sub.2 Me 
H 
60 H H 5'-NO.sub.2 
H 
61 H H 5'-SO.sub.2 CH.sub.3 
H 
62 H H 5'-OCOCH.sub.3 
H 
63 H H 5'-CH.sub.3 
H 
64 H H 5'-OEt H 
65 H H 5'-OMe H 
66 5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
H H 6'-CO.sub.2 Me 
67 5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
H H 6'-NO.sub.2 
68 5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
H H 6'-OMe 
69 5-OCH.sub. 2 CH.sub.2 CH.sub.2 (i-Pr) 
H H 6'-CO.sub.2 Me 
70 5-OCH.sub.2 CH.sub.2 CH.sub.2 (i-Pr) 
H H 6'-NO.sub.2 
71 5-OCH.sub.2 CH.sub.2 CH.sub.2 (i-Pr) 
H H 6'-OMe 
72 H H 2'-F 6'-F 
73 H 6-OCH.sub.2 CHCH.sub.2 
2'-F 6'-F 
74 H 6-OCH.sub.2 Ph 
2'-F 6'-F 
75 5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
H 2'-F 6'-F 
75a 
H H H H 
75b 
H H 2'-CH.sub.2 CHCH.sub.2 
6'-CO.sub.2 Me 
75c 
H H H 6'-Ph 
__________________________________________________________________________ 
TABLE 2 
__________________________________________________________________________ 
##STR33## 
Ex. 
No. W n Y R.sup.1 R.sup.4 
__________________________________________________________________________ 
76 H.sub.2 N 
1 bond 
H 6'-OCH.sub.2 CO.sub.2 H 
77 H.sub.2 N 
1 bond 
H 6'-CO.sub.2 Me 
78 H.sub.2 N 
1 bond 
H 6'-OMe 
79 H.sub.2 N 
1 bond 
H 6'-NO.sub.2 
80 H.sub.2 N 
1 bond 
H 6'-OEt 
81 H.sub.2 N 
1 bond 
H 5'-OMe 
82 H.sub.2 N 
1 bond 
6-OCH.sub.2 CH CH.sub.2 
6'-OMe 
83 H.sub.2 N 
1 bond 
6-OCH.sub.2 Ph 
6'-OMe 
84 H.sub.2 N 
1 bond 
6-OCH.sub.2 CH.sub.2 (i-Pr) 
6'-OMe 
85 CH.sub.3 NH 
1 bond 
H 6'-OMe 
86 CH.sub.3 NH 
1 bond 
H 6'-OEt 
87 CH.sub.3 NH 
1 bond 
H 6'CO.sub.2 Me 
88 CH.sub.3 NH 
1 bond 
H 6'-NO.sub.2 
89 CH.sub.3 NH 
1 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
90 CH.sub.3 NH 
1 bond 
6-OCH.sub.2 Ph 
6'-OMe 
91 H.sub.2 N 
2 bond 
H 6'-OEt 
92 H.sub.2 N 
2 bond 
H 6'-OMe 
93 H.sub.2 N 
2 bond 
H 6'-NO.sub.2 
94 H.sub.2 N 
2 bond 
H 6'CO.sub.2 Me 
95 H.sub.2 N 
2 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
96 CH.sub.3 NH 
2 bond 
H 6'-OMe 
97 CH.sub.3 NH 
2 bond 
H 6'-NO.sub.2 
98 CH.sub.3 NH 
2 bond 
H 6'-CO.sub.2 Me 
99 CH.sub.3 NH 
2 bond 
6-OCH.sub.2 CHCH.sub. 2 
6'-OMe 
100 CH.sub.3 NH 
2 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-NO.sub.2 
101 H.sub.2 N 
3 bond 
H 6'-CO.sub.2 Et 
102 H.sub.2 N 
3 bond 
H 6'-OMe 
103 H.sub.2 N 
3 bond 
H 6'NO.sub.2 
104 H.sub.2 N 
3 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
105 H.sub.2 N 
3 bond 
6-OCH.sub.2 Ph 
6'-OMe 
106 H.sub.2 N 
3 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-NO.sub.2 
107 CH.sub.3 NH 
3 bond 
H 6'-CO.sub.2 Et 
108 CH.sub.3 NH 
3 bond 
H 6'-NO.sub.2 
109 CH.sub.3 NH 
3 bond 
H 6'-OMe 
110 CH.sub.3 NH 
3 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
111 CH.sub.3 NH 
3 bond 
6-OCH.sub.2 Ph 
6'-OMe 
112 H.sub.2 NC(NH)NH 
1 bond 
H 6'-OMe 
113 H.sub.2 NC(NH)NH 
1 bond 
H 6'-NO.sub.2 
114 H.sub.2 NC(NH)NH 
1 bond 
H 6'-CO.sub.2 Me 
115 H.sub.2 NC(NH)NH 
1 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
116 H.sub.2 NC(NH)NH 
1 bond 
6-OCH.sub.2 Ph 
6'-OMe 
117 HN(CH.sub. 2 CH.sub.2).sub.2 N 
0 bond 
H 6'-CO.sub.2 Et 
118 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-CO.sub.2 Me 
119 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'NO.sub.2 
120 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-OMe 
121 CH.sub.3 NH 
2 O H 6'-OMe 
122 HN(CH.sub.2 CH.sub.2)N 
O 0 6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
123 HN(CH.sub.2 CH.sub.2)N 
O 0 6-OCH.sub.2 Ph 
6'-OMe 
124 HN(CH.sub.2 CH.sub.2)N 
O 0 5-OCH.sub.2 CH.sub.2 CHMe2 
6'-OMe 
125 HN(CH.sub.2 CH.sub.2)N 
O 0 5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
6'-OMe 
125a 
NH.sub.2 1 bond 
H H 
__________________________________________________________________________ 
TABLE 3 
__________________________________________________________________________ 
##STR34## 
Ex. 
No. W n Y R.sup.1 R.sup.4 
__________________________________________________________________________ 
126 H.sub.2 N 
2 O H H 
127 H.sub.2 N 
2 O H 6'-NO.sub.2 
128 H.sub.2 N 
2 O H 6'-OMe 
129 H.sub.2 N 
2 O H 6'-CO.sub.2 Me 
130 CH.sub.3 NH 
2 O H 6'-OMe 
131 CH.sub.3 NH 
2 O H 6'-NO.sub.2 
132 CH.sub.3 NH 
2 O H 6'-CO.sub.2 Me 
133 H.sub.2 N 
2 O 6-OCH.sub.2 CHCH.sub. 2 
6'-OMe 
134 CH.sub.3 NH 
2 O 6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
135 H.sub.2 NC(NH)NH 
1 bond 
H 6'-OMe 
136 H.sub.2 NC(NH)NH 
1 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
137 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-OMe 
138 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
139 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-OMe 
140 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
141 H.sub.2 NC(NH)NH 
0 bond 
H 6'-OMe 
142 H.sub.2 NC(NH)NH 
0 bond 
H 6'-CO.sub.2 Me 
143 H.sub.2 NC(NH)NH 
0 bond 
H 6'-NO.sub.2 
144 H.sub.2 NC(NH)NH 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-NO.sub.2 
145 H.sub.2 NC(NH)NH 
13 bond 
6-OCH.sub.2 Ph 
6'-OMe 
__________________________________________________________________________ 
TABLE 4 
__________________________________________________________________________ 
##STR35## 
Ex. 
No. W n Y P R.sup.4 
__________________________________________________________________________ 
146 H.sub.2 N 2 O 0 6'-OMe 
147 H.sub.2 N 2 O 1 6'-OMe 
148 H.sub.2 N 2 O 2 6'-OMe 
149 H.sub.2 N 2 O 0 6'-NO.sub.2 
150 H.sub.2 N 2 O 1 6'-NO.sub.2 
151 H.sub.2 N 2 O 2 6'-NO.sub.2 
152 H.sub.2 N 2 O 0 6'-CO.sub.2 Me 
153 H.sub.2 N 2 O 1 6'-CO.sub.2 Me 
154 H.sub.2 N 2 O 2 6'-CO.sub.2 Me 
155 CH.sub.3 NH 2 O 2 6'-OMe 
156 CH.sub.3 NH 2 O 1 6'-OMe 
157 CH.sub.3 NH 2 O 0 6'-OMe 
158 CH.sub.3 NH 2 O 2 6'-NO.sub.2 
159 CH.sub.3 NH 2 O 1 6'-NO.sub.2 
160 CH.sub.3 NH 2 O 0 6'-NO.sub.2 
161 CH.sub.3 NH 2 O 2 6'-CO.sub.2 Me 
162 CH.sub.3 NH 2 O 1 6'-CO.sub.2 Me 
163 CH.sub.3 NH 2 O 0 6'-CO.sub.2 Me 
164 H.sub.2 NC(NH)NH 
1 bond 2 6'-OMe 
165 H.sub.2 NC(NH)NH 
1 bond 1 6'-OMe 
166 H.sub.2 NC(NH)NH 
1 bond 0 6'-OMe 
167 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 2 6'-OMe 
168 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 1 6'-OMe 
169 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 0 6'-OMe 
170 H.sub.2 N(CH.sub.2 CH.sub.2)CH 
0 bond 2 6'-OMe 
171 H.sub.2 N(CH.sub.2 CH.sub.2)CH 
0 bond 1 6'-OMe 
172 H.sub.2 N(CH.sub.2 CH.sub.2)CH 
0 bond 0 6'-OMe 
173 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 2 6'-NO.sub.2 
174 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 1 6'-NO.sub.2 
175 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 0 6'-NO.sub.2 
__________________________________________________________________________ 
TABLE 5 
__________________________________________________________________________ 
##STR36## 
Ex. 
No. W n Y p R.sup.4 
__________________________________________________________________________ 
176 H.sub.2 N 2 O 0 6'-OMe 
177 H.sub.2 N 2 O 1 6'-OMe 
178 H.sub.2 N 2 O 2 6'-OMe 
179 H.sub.2 N 2 O 0 6'-NO.sub.2 
180 H.sub.2 N 2 O 1 6'-NO.sub.2 
181 H.sub.2 N 2 O 2 6'-NO.sub.2 
182 H.sub.2 N 2 O 0 6'-CO.sub.2 Me 
183 H.sub.2 N 2 O 1 6'-CO.sub.2 Me 
184 H.sub.2 N 2 O 2 6'-CO.sub.2 Me 
185 CH.sub.3 NH 
2 O 2 6'-OMe 
186 CH.sub.3 NH 
2 O 1 6'-OMe 
187 CH.sub.3 NH 
2 O 0 6'-OMe 
188 CH.sub.3 NH 
2 O 2 6'-NO.sub.2 
189 CH.sub.3 NH 
2 O 1 6'-NO.sub.2 
190 CH.sub.3 NH 
2 O 0 6'-NO.sub.2 
191 CH.sub.3 NH 
2 O 2 6'-CO.sub.2 Me 
192 CH.sub.3 NH 
2 O 1 6'-CO.sub.2 Me 
193 CH.sub.3 NH 
2 O 0 6'-CO.sub.2 Me 
194 H.sub.2 NC(NH)NH 
1 bond 
2 6'-OMe 
195 H.sub.2 NC(NH)NH 
1 bond 
1 6'-OMe 
196 H.sub.2 NC(NH)NH 
1 bond 
0 6'-OMe 
197 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
2 6'-OMe 
198 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
1 6'-OMe 
199 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
0 6'-OMe 
200 H.sub.2 N(CH.sub.2 CH.sub.2)CH 
0 bond 
2 6'-OMe 
201 H.sub.2 N(CH.sub.2 CH.sub.2)CH 
0 bond 
1 6'-OMe 
202 H.sub.2 N(CH.sub.2 CH.sub.2)CH 
0 bond 
0 6'-OMe 
203 H.sub.2 NC(NH)NH 
1 bond 
2 6'-NO.sub.2 
204 H.sub.2 NC(NH)NH 
1 bond 
1 6'-NO.sub.2 
205 H.sub.2 NC(NH)NH 
1 bond 
0 6'-NO.sub.2 
206 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
2 6'-NO.sub.2 
207 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
1 6'-NO.sub.2 
208 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
0 6'-NO.sub.2 
__________________________________________________________________________ 
TABLE 6 
__________________________________________________________________________ 
##STR37## 
Ex. 
No. W n Y R.sup.1 R.sup.4 
__________________________________________________________________________ 
211 H.sub.2 N 
2 O H 6'-OMe 
212 H.sub.2 N 
2 O 6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
213 H.sub.2 N 
2 O 6-OCH.sub.2 Ph 
6'-OMe 
214 H.sub.2 N 
2 O H 6'-NO.sub.2 
215 H.sub.2 N 
2 O 6-OCH.sub.2 CHCH.sub.6 
6'-NO.sub.2 
216 H.sub.2 N 
2 O 6-OCH.sub.2 Ph 
6'-NO.sub.2 
217 H.sub.2 N 
2 O H 6' -CO.sub.2 Me 
218 H.sub.2 N 
2 O 6-OCH.sub.2 CHCH.sub.2 
6'-CO.sub.2 Me 
219 H.sub.2 N 
2 O 6-OCH.sub.2 Ph 
6'-CO.sub.2 Me 
220 CH.sub.3 NH 
2 O H 6'-OMe 
221 CH.sub.3 NH 
2 O 6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
222 CH.sub.3 NH 
2 O 6-OCH.sub.2 Ph 
6'-OMe 
223 H.sub.2 NC(NH)NH 
1 bond 
H 6'-OMe 
224 H.sub.2 NC(NH)NH 
1 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
225 H.sub.2 NC(NH)NH 
1 bond 
6-OCH.sub.2 Ph 
6'-OMe 
226 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-OMe 
227 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
228 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
6'-OMe 
229 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-OMe 
230 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
231 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
6'-OMe 
232 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-NO.sub.2 
233 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-NO.sub.2 
234 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
6-NO.sub.2 
235 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
6'-OMe 
__________________________________________________________________________ 
TABLE 7 
__________________________________________________________________________ 
##STR38## 
Ex. 
No. W n Y R.sup.4 
X m R.sup.7 
__________________________________________________________________________ 
240 NH.sub.2 
2 3-bond 1'-NO.sub.2 
2'-O 
1 H 
241 NH.sub.2 
4 4-bond H 1'-O 
1 H 
242 NH.sub.2 
2 3-O H 1'-O 
2 H 
243 NH.sub.2 
4 4-bond H 1'-bond 
2 H 
244 NH.sub.2 
1 3-bond H 2'-O 
1 H 
245 NH.sub.2 
1 4-bond H 1'-bond 
2 H 
246 NH.sub.2 
1 3-bond H 1'-O 
1 H 
247 NH.sub.2 
1 
##STR39## 
6'-CO.sub.2 Et 
1'-O 
1 H 
248 NMe.sub.2 
2 3-O H 2'-bond 
0 H 
249 NH.sub.2 
2 3-O 6'-OEt 
1'-O 
1 n-hexyl 
250 NH.sub.2 
1 4-bond 6'-NO.sub.2 
1'-O 
1 H 
251 NH.sub.2 
3 2-O 6'-CO.sub.2 Et 
1'-O 
1 H 
252 NH.sub.2 
2 3-O 1'-OMe 
2'-bond 
1 H 
__________________________________________________________________________ 
TABLE 8 
__________________________________________________________________________ 
##STR40## 
Ex. 
No. W n Y R.sup.1 R.sup.3 
__________________________________________________________________________ 
300 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-OMe 
301 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
6'-OMe 
302 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-OMe 
303 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
6'-OMe 
304 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub. 2 CH.sub.2 (i-Pr) 
6'-OMe 
305 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-ON.sub.2 
306 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
6'-ON.sub.2 
307 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-ON.sub.2 
308 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
6'-ON.sub.2 
309 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 (i-Pr) 
6'ON.sub.2 
310 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 6'-CO.sub.2 Me 
311 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
6'-CO.sub.2 Me 
312 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
6'-CO.sub.2 Me 
313 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
6'-CO.sub.2 Me 
314 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 (i-Pr) 
6'-CO.sub.2 Me 
315 H.sub.2 N 
2 O H 6'-OMe 
316 H.sub.2 N 
2 O H 6'-NO.sub.2 
317 H.sub.2 N 
2 O H 6'-CO.sub.2 Me 
318 H.sub.2 N 
2 O 6-OCH.sub.2 Ph 
6'-OMe 
319 H.sub.2 N 
2 O 5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
6'-OMe 
320 H.sub.2 N 
2 O 6-OCH.sub.2 Ph 
6'-NO.sub.2 
321 H.sub.2 N 
2 O 6-OCH.sub.2 Ph 
6'-CO.sub.2 Me 
322 H.sub.2 N 
2 bond 
H 6'-NO.sub.2 
__________________________________________________________________________ 
TABLE 9 
__________________________________________________________________________ 
##STR41## 
Ex. 
No. W n Y R.sup.1 R.sup.3 
__________________________________________________________________________ 
330 H.sub.2 N 
2 O H H 
331 H.sub.2 N 
2 O H 1'-OMe 
332 H.sub.2 N 
2 O H 1'-NO.sub.2 
333 H.sub.2 N 
2 O H 1'-CO.sub.2 Me 
334 H.sub.2 N 
2 O H 1'-COPh 
335 H.sub.2 N 
2 O H 1'-SO.sub.2 Ph 
336 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H H 
337 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 1'-OMe 
338 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 1'-NO.sub.2 
339 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 1'-CO.sub.2 Me 
340 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 1'-COPh 
341 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
H 1'-SO.sub.2 Ph 
342 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
1'-OMe 
343 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
1'-OMe 
344 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
1'-OMe 
345 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 (i-Pr) 
1'-OMe 
346 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 Ph 
1'-SO.sub.2 Ph 
347 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
6-OCH.sub.2 CHCH.sub.2 
1'-SO.sub.2 Ph 
348 HN(CH.sub.2 CH.sub.2).sub.2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 Ph 
1'-SO.sub.2 Ph 
349 HN(CH.sub.2 CH.sub.2).sub. 2 N 
0 bond 
5-OCH.sub.2 CH.sub.2 CH.sub.2 (i-Pr) 
1'-SO.sub.2 Ph 
__________________________________________________________________________