Note: Descriptions are shown in the official language in which they were submitted.
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INHIBITORS OF FACTOR Xa
Related Applications
This application claims benefit of priority under 35 USC ~ 119(e) to U.S.
Provisional Application No. 60/135,838 filed on May 24, 1999, which is herein
incorporated in its entirety by reference.
Field of the Invention
This invention relates to novel compounds which are potent and highly
selective inhibitors of isolated factor Xa or when assembled in the
prothrombinase
complex..-These compounds show selectivity for factor Xa versus other
proteases of
the coagulation (e.g. thrombin, fVIIa, flXa) or the fibrinolytic cascades
(e.g.
plasminogen activators, plasmin). In another aspect, the present invention
relates to
novel monoamidino-containing compounds, their pharmaceutically acceptable
salts,
and pharmaceutically acceptable compositions thereof which are useful as
potent
' and specific inhibitors of blood coagulation in mammals. In yet another
aspect, the
invention relates to methods for using these inhibitors as therapeutic agents
for
disease states in mammals characterized by coagulation disorders.
Background of the Invention
Hemostasis, the control of bleeding, occurs by surgical means, or by the
. physiological properties of vasoconstriction and coagulation. This invention
is
particularly concerned with blood coagulation and ways in which it assists in
maintaining the integrity of mammalian circulation after injury, inflammation,
disease, congenital defect, dysfunction or other disruption. Although
platelets and
blood coagulation are both involved in thrombus formation, certain components
of
the coagulation cascade are primarily responsible for the amplification or
acceleration of the processes involved in platelet aggregation and fibrin
deposition.
Thrombin is a key enzyme in the coagulation cascade as well as in
hemostasis. Thrombin plays a central role in thrombosis through its ability to
catalyze the conversion of fibrinogen into fibrin and through its potent
platelet
activation activity. Direct or indirect inhibition of thrombin activity has
been the
focus of a variety of recent anticoagulant strategies as reviewed by Claeson,
G.,
"Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of
Thrombin
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and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol.
_5,
411-436 (1994). Several classes of anticoagulants currently used in the clinic
directly or indirectly affect thrombin (i.e. heparins, low-molecular weight
heparins,
heparin-like compounds and coumarins).
A prothrombinase complex, including Factor Xa (a serine protease, the
activated form of its Factor X precursor and a member of the calcium ion
binding,
gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation
glycoprotein family), converts the zymogen prothrombin into the active
procoagulant thrombin. Unlike thrombin, which acts on a variety of protein
substrates as well as at a specific receptor, factor Xa appears to have a
single
physiologic substrate, namely prothrombin. Since one molecule of factor Xa may
be
able to generate up to 138 molecules of thrombin (Elodi et al., Thromb. Res.
15, 61~7-
619 (1979)); direct inhibition of factor Xa as a way of indirectly inhibiting
the
formation of thrombin may be an efficient anticoagulant strategy. Therefore,
it has
been suggested that compounds which selectively inhibit factor Xa may be
useful as
in vitro diagnostic agents, or for therapeutic administration in certain
thrombotic
disorders, see e.g., WO 94/13693.
Polypeptides derived from hematophagous organisms have been reported
which are highly potent and specific inhibitors of factor Xa. United States
Patent
4,588,587 describes anticoagulant activity in the saliva of the Mexican leech,
Haementeria o~cinalis. A principal component of this saliva was shown to be
the
polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al., "The
Amino
Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a
Repeated
Internal Structure", J. Biol. Chem., 263, 10162-10167 (1988). Another potent
and
highly specific inhibitor of Factor Xa, called tick anticoagulant peptide
(TAP), has
been isolated from the whole body extract of the soft tick Ornithidoros
moubata, as
reported by Waxman, L., et al., "Tick Anticoagulant Peptide (TAP) is a Novel
Inhibitor of Blood Coagulation Factor Xa" Science, ~, 593-596 (1990).
Factor Xa inhibitory compounds which are not large polypeptide-type
inhibitors have also been reported including: Tidwell, R.R. et al.,
"Strategies for
Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus
Thrombin
Inhibitors", Thromb. Res., l~, 339-349 (1980); Turner, A.D. et al., "p-Amidino
Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin",
Biochemistry,
~, 4929-4935 (1986); Hitomi, Y. et al., "Inhibitory Effect of New Synthetic
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Protease Inhibitor (FUT-175) on the Coagulation System", Haemostasis, ~, 164-
168 (1985); Sturzebecher, J. et al., "Synthetic Inhibitors of Bovine Factor Xa
and
Thrombin. Comparison of Their Anticoagulant Efficiency", Thromb. Res., ~, 245-
252 (1989); Kam, C.M. et al., "Mechanism Based Isocoumarin Inhibitors for
Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants",
Biochemistry, ~, 2547-2557 (1988); Hauptmann, J. et al., "Comparison of the
Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa
Inhibitors", Thromb. Haemost., ~3, 220-223 (1990); and the like.
Others have reported Factor Xa inhibitors which are small molecule organic
compounds, such as nitrogen containing heterocyclic compounds which have
amidino substituent groups, wherein two functional groups of the compounds can
bind to Factor Xa at two of its active sites. For example, WO 98/28269
describes
pyrazole compounds having a terminal C(=NH)-NHZ group; WO 97/21437 describes
benzimidazole compounds substituted by a basic radical which are connected to
a
naththyl group via a straight or branched chain alkylene,-C(=O) or -S(=O)2
bridging
group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-
piperidine and 4-phenoxy-N-alkylamidino-piperidine group connected to a 3-
amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295
describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group
connected to an amidinonaphthyl group via a substituted or unsubstituted
sulfonamide or carboxamide bridging group.
There exists a need for effective therapeutic agents for the regulation of
hemostasis, and for the prevention and treatment of thrombus formation and
other
pathological processes in the vasculature induced by thrombin such as
restenosis and
inflammation. In particular, there continues to be a need for compounds which
selectively inhibit factor Xa or its precursors. Compounds that have different
combinations of bridging groups and functional groups than compounds
previously
discovered are needed, particularly compounds which selectively or
preferentially
bind to Factor Xa. Compounds with a higher degree of binding to Factor Xa than
to
thrombin are desired, especially those compounds having good bioavailability
and/or
solubility.
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Summarv of the Invention
The present invention relates to novel compounds which inhibit factor Xa,
their pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug
derivatives, and pharmaceutically acceptable compositions thereof which have
particular biological properties and are useful as potent and specific
inhibitors of
blood coagulation in mammals. In another aspect, the invention relates to
methods
of using these inhibitors as diagnostic reagents or as therapeutic agents for
disease
states in mammals which have coagulation disorders, such as in the treatment
or ,
prevention of any thrombotically mediated acute coronary or cerebrovascular
syndrome, any thrombotic syndrome occurnng in the venous system, any
coagulopathy, and any thrombotic complications associated with extracorporeal
circulation or instrumentation, and for the inhibition of coagulation in
biological
samples.
In certain embodiments, this invention relates to novel compounds which are
potent and highly selective inhibitors of isolated factor Xa when assembled in
the
prothrombinase complex. These compounds show selectivity for factor Xa versus
other proteases of the coagulation cascade (e.g. thrombin, etc.) or the
fibrinolytic
cascade, and are useful as diagnostic reagents as well as antithrombotic
agents.
In a preferred embodiment, the present invention provides a compound of the
formula I:
A-Y-D-E-G-J-Z-L
wherein:
A is selected from:
(a) C,-C6 alkyl;
(b) C3-C8 cycloalkyl;
(c) phenyl, which is independently substituted with 0-2 R' subsituents;
(d) naphthyl, which is independently substituted with 0-2 R'
subsituents;and
(e) a monocyclic or fused bicyclic heterocyclic ring system having from
S to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
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selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R' subsituents;
R' is selected from:
Halo, C,~alkyl, Cz_6alkenyl, CZ_balkynyl, C3_acycloalkyl, Co~alkylC3_
gcycloalkyl,-CN, -NOz, (CHZ)mNRZR3, SOzNR2R3, SOZR2, CF3, OR2, and a S-
6 membered aromatic heterocyclic system containing from 1-4 heteroatoms
selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic
heterocyclic system may be independently replaced with a member selected
from the group consisting of halo, C,-C4-alkyl, -CN C,~,alkyl, Cz_6alkenyl,
Cz_
6alkynyl, C3_8cycloalkyl, Co~alkylC3_8cycloalkyl and -NOZ;
RZ and R' are independently selected from the group consisting of
H, C,~alkyl, Cz_balkenyl, CZ_6alkynyl, C3_8cycloalkyl,
Co~,alkylC3_8cycloalkyl,
Co~alkylphenyl and C~allcylnaphthyl, wherein from 1-4 hydrogen atoms on
the ring atoms of the phenyl and naphthyl moieties may be independently
replaced with a member selected from the group consisting of halo, C,~alkyl,
CZ_6alkenyl, Cz_6alkynyl, C3_$cycloalkyl, C~alkylC3_8cycloalkyl, -CN, and
-NOz
m is an integer of 0-2;
Y is a member selected from the group consisting of
a direct link, -C(=O)-, -N(R4)-, -C(=O)-N(R4)-, -N(R4)-C(=O)-, -SOz-, -O-,
-SOZ-N(R4)- and N(R4)-SOZ ;
R4 is selected from:
H, C,~alkyl, Cz_6alkenyl, CZ_6alkynyl, C3_gcycloalkyl, Co~alkylC3_gcycloalkyl,
Co~alkylphenyl and C~alkylnaphthyl, wherein from 1-4 hydrogen atoms on
the ring atoms of the phenyl and naphthyl moieties may be independently
replaced with a member selected from the group consisting of halo, C,~alkyl,
CZ_6alkenyl, Cz_6alkynyl, C3_8cycloalkyl, Co~alkylC3_gcycloalkyl, -CN, and
_NOz~.
D is a direct link or is a member selected from the group consisting of
(a) phenyl, which is independently substituted with 0-2 R'a subsituents;
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(b) naphthyl, which is independently substituted with 0-2 R'a subsituents;
and
(c) a monocyclic or fused bicyclic heterocyclic ring system having from
to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
5 selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R'e subsituents;
R'a is selected from:
Halo, C,~,alkyl, Cz_6alkenyl, Cz_6alkynyl, C3_$cycloalkyl, C~alkylC3_
8cycloalkyl, -CN, -NOz, (CHz)mNRzaR38, SOZNRzaR3a, SOZRze, CF3, ORze, and
a 5-6 membered aromatic heterocyclic system containing from 1-4
heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on
the aromatic heterocyclic system may be independently replaced with a
member selected from the group consisting of halo, C,~alkyl, Cz_6alkenyl, Cz_
balkynyl, C3_8cycloalkyl, C~alkylC3_$cycloalkyl, -CN and -NOz.
Rza and R38 are independently selected from the group consisting of
H, C,~allcyl, Cz_6alkenyl, Cz_6alkynyl, C3_8cycloalkyl,
Co~alkylC3_gcycloalkyl,
Co~alkylphenyl and C~alkylnaphthyl, wherein from 1-4 hydrogen atoms on
the ring atoms of the phenyl and naphthyl moieties may be independently
replaced with a member selected from the group consisting of halo, C,~alkyl,
Cz_6alkenyl, Cz_balkynyl, C3_8cycloalkyl, Co~alkylC3_8cycloalkyl, -CN and
_NOz~.
E is a member selected from the group consisting of
-N(Rs)_C(=O)_, -C(=O)_N(RS)-, -N(RS)-C(-O)_N(R6)-, -SOz_N(RS)-,
-N(RS)-SOz-N(R6)- and -N(RS)-SOz N(R6)-C(=O)-;
RS and R6 are independently selected from:
H, C,~alkyl, Cz_6alkenyl, Cz_6alkynyl, C3_gcycloalkyl, C~alkylC3_gcycloalkyl,
C~alkylphenyl, Co~alkylnaphthyl, C~alkylheteroaryl, C,~alkylCOOH and
C,~alkylCOOC,~alkyl, wherein from 1-4 hydrogen atoms on the ring atoms
of the phenyl, naphthyl and heteroaryl moieties may be independently
replaced with a member selected from the group consisting of halo, C,~alkyl,
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CZ_balkenyl, CZ_6alkynyl, C3_8cycloalkyl, C~alkylC3_$cycloalkyl, -CN and
-NOz
G is a member selected from the group consisting of:
a direct link, -CR'R$- and -CR'aRga-CR'aRgb-
wherein R', R8, R'a, RBa, R'~ and R8b are independently a member selected from
from
the group consisting of
hydrogen, C,_4alkyl, Cz_6alkenyl, Cz_6alkynyl, C3_8cycloalkyl, C°~alkyl-
C3_
8cycloalkyl, C°~alkylphenyl, C°~,alkylnaphthyl, -OR9, -
C~,,alkylCOOR9,
-Co-aalkylC(=O)NR9R'o, -Co-aalkYlC(=O)NR9-CHZ-CHZ O-R'°,
-Co~alkylC(=O)NR9(-CHZ-CHz-O-R'°-)2, -N(R9)COR'°, -
N(R9)C(=O)R'°,
-N(R9)SOZR'°, and a naturally occurring or synthetic amino acid side
chain,
wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and
naphthyl moieties may be independently replaced with a member selected
from the group consisting of halo, C,~alkyl, CZ_6alkenyl, Cz_6alkynyl, C3_
8cycloalkyl, C°~alkyl-C3_$cycloalkyl, -CN and -NOz;
R9 and R'° are independently selected from:
H, C,~,alkyl, C~alkylphenyl and C°~alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may
be independently replaced with a member selected from the group consisting
of halo, C,~alkyl, CZ_6alkenyl, CZ_6alkynyl, C3_8cycloalkyl, Co~alkyl-C3_
gcycloalkyl, -CN and -NO2, and wherein R9 and R'° taken together can
form a
5-8 membered heterocylic ring;
J is a member selected from the group consisting of
Itta ~Rtt Dtta tt
,R
0-2 ~ ~r~2 and
Rtt b Rtt b N'
wherein the ring carbons or second ring nitrogen of the amino ring structure
and/or
the ring carbons on the alkylene bridging groups attached to the amino ring
structure
may be independently substituted by a total of 0 to 4 R", R"a, R"b and R"~
groups;
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R", R"a, R"b and R"° are independently a member selected from the
group
consisting of
hydrogen, -OH, -O-C,~alkyl, -C,~alkyl, CZ_6alkenyl, CZ_6alkynyl, C3_
8cycloalkyl, C~alkyl-C,_$cycloalkyl, Co~alkylphenyl, Co~alkylnaphthyl,
Co.~alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from
the group consisting of N, O and S, CHZCOOC,~alkyl,
CHZCOOC,~alkylphenyl and CHZCOOC,~alkylnaphthyl;
Z is a member selected from the group consisting of
(a) phenyl, which is independently substituted with 0-2 R'b subsituents;
(b) naphthyl, which is independently substituted with 0-2 R'b subsituents;
and
(c) a monocyclic or fused bicyclic heterocyclic ring system having from
5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R'b subsituents;
R'b is selected from:
Halo, C,~alkyl, CZ_6alkenyl, CZ_6alkynyl, C3_$cycloalkyl, Co~alkylC3_
8cycloalkyl, -CN, -NOz, NRZbR3b~ SOZNR2bR3b~ SOZRzb, CF3, ORZb, O-CHZ
CHZ-ORZb, O-CHZ-COORzb, N(RZb)-CHZ_CHz-ORzb, N(-CHZ-CHZ-ORZb)2,
N(Rzb)-C(=O)R3b, N(RZb)-SOZ-R3b, and a 5-6 membered aromatic heterocyclic
system containing from 1-4 heteroatoms selected from N, O and S, wherein
from 1-4 hydrogen atoms on the aromatic heterocyclic system may be
independently replaced with a member selected from the group consisting of
halo, C,~alkyl, Cz_6alkenyl, CZ_6alkynyl, C3_8cycloalkyl, Co~alkylC3_
8cycloalkyl, -CN and -NOZ;
RZb and R3b are independently selected from the group consisting of
H, C,~alkyl, Cz_6alkenyl, Cz_6alk5myl, C3_8cycloalkyl,
Co~alkylC3_$cycloallcyl,
C~alkylphenyl and Co~alkylnaphthyl, wherein from 1-4 hydrogen atoms on
the ring atoms of the phenyl and naphthyl moieties may be independently
replaced with a member selected from the group consisting of halo, C,~alkyl,
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_g_
Cz_6alkenyl, Cz_6alkynyl, C3_$cycloalkyl, C~alkylC3_gcycloalkyl, -CN and
_NOz
L is selected from:
H~ _CN~ C~-O~yzRis~ ~CHz)~WzR~3~ L,~_~12~~12R13~ yzR~s~ OR'z,
-yzC~-yz~yzR~3~ and NR'zC(=NR'z)-R's;
R'z and R'3 are independently selected from:
hydrogen, -OR'4, -NR'4R'S, C,~alkyl, Co~alkylphenyl, C~alkylnaphthyl,
COOC,~alkyl, COO-Co~alkylphenyl and COO-Co~alkylnaphthyl, wherein
from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl
moieties may be independently replaced with a member selected from the
group consisting of halo, C,~alkyl, Cz_6alkenyl, Cz_6alkynyl, C3_8cycloalkyl,
Co~alkylC3_8cycloalkyl, -CN, and -NOz;
R'4 and R'S are independently selected from:
H, C,~,alkyl, Cz_6alkenyl, Cz_balkynyl, C3_$cycloalkyl,
Co~alkylC3_gcycloalkyl,
Co~alkylphenyl and Co..4alkylnaphthyl, wherein from 1-4 hydrogen atoms on
the ring atoms of the phenyl and naphthyl moieties may be independently
replaced with a member selected from the group consisting of halo, C,~alkyl,
Cz_6alkenyl, Cz_6alk3myl, C3_gcycloalkyl, C~alkylC3_gcycloalkyl, -CN, and
-NOz;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In certain aspects of this invention, compounds are provided which are useful
as diagnostic reagents. In another aspect, the present invention includes
pharmaceutical compositions comprising a pharmaceutically effective amount of
the
compounds of this invention and a pharmaceutically acceptable carrier. In yet
another aspect, the present invention includes methods comprising using the
above
compounds and pharmaceutical compositions for preventing or treating disease
states characterized by undesired thrombosis or disorders of the blood
coagulation
process in mammals, or for preventing coagulation in biological samples such
as, for
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example, stored blood products and samples. Optionally, the methods of this
invention comprise administering the pharmaceutical composition in combination
with an additional therapeutic agent such as an antithrombotic and/or a
thrombolytic
agent and/or an anticoagulant.
The preferred compounds also include their pharmaceutically acceptable
isomers, hydrates, solvates, salts and prodrug derivatives.
Detailed Description of the Invention
Definitions
In accordance with the present invention and as used herein, the following
terms are defined with the following meanings, unless explicitly stated
otherwise.
The term "alkenyl" refers to a trivalent straight chain or branched chain
unsaturated aliphatic radical. The term "alkinyl" (or "alkynyl") refers to a
straight or
branched chain aliphatic radical that includes at least two carbons joined by
a triple
bond. If no number of carbons is specified alkenyl and alkinyl each refer to
radicals ,
having from 2-12 carbon atoms.
The term "alkyl" refers to saturated aliphatic groups including straight-
chain,
branched-chain and cyclic groups having the number of carbon atoms specified,
or if
no number is specified, having up to 12 carbon atoms. The term "cycloalkyl" as
used herein refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14
carbon
atoms and preferably 3 to 7 carbon atoms.
As used herein, the terms "carbocyclic ring structure " and " C3_,6
carbocyclic
mono, bicyclic or tricyclic ring structure" or the like are each intended to
mean
stable ring structures having only carbon atoms as ring atoms wherein the ring
structure is a substituted or unsubstituted member selected from the group
consisting
of a stable monocyclic ring which is aromatic ring ("aryl") having six ring
atoms; a
stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring;
a
stable bicyclic ring structure having a total of from 7 to 12 ring atoms in
the two
rings wherein the bicyclic ring structure is selected from the group
consisting of ring
structures in which both of the rings are aromatic, ring structures in which
one of the
rings is aromatic and ring structures in which both of the rings are non-
aromatic; and
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a stable tricyclic ring structure having a total of from 10 to 16 atoms in the
three
rings wherein the tricyclic ring structure is selected from the group
consisting of
ring structures in which three of the rings are aromatic, ring structures in
which two
of the rings are aromatic and ring structures in which three of the rings are
non-
aromatic. In each case, the non-aromatic rings when present in the monocyclic,
bicyclic or tricyclic ring structure may independently be saturated, partially
saturated
or fully saturated. Examples of such carbocyclic ring structures include, but
are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl,
cyclooctyl,
[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or
tetrahydronaphthyl (tetralin). Moreover, the ring structures described herein
may be
attached to one or more indicated pendant groups via any carbon atom which
results
in a stable structure. The term "substituted" as used in conjunction with
carbocyclic
ring structures means that hydrogen atoms attached to the ring carbon atoms of
ring
structures described herein may be substituted by one or more of the
substituents
indicated for that structure if such substitutions) would result in a stable
compound.
The term "aryl" which is included with the term "carbocyclic ring structure"
refers to an unsubstituted or substituted aromatic ring, substituted with one,
two or
three substituents selected from loweralkoxy, loweralkyl, loweralkylamino,
hydroxy,
halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde,
carboxyl,
carboalkoxy and carboxamide, including but not limited to carbocyclic aryl,
heterocyclic aryl, and biaryl groups and the like, all of which may be
optionally
substituted. Preferred aryl groups include phenyl, halophenyl,
loweralkylphenyl,
napthyl, biphenyl, phenanthrenyl and naphthacenyl.
The term "arylalkyl" which is included with the term "carbocyclic aryl"
refers to one, two, or three aryl groups having the number of carbon atoms
designated, appended to an alkyl group having the number of carbon atoms
designated. Suitable arylalkyl groups include, but are not limited to, benzyl,
picolyl,
naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may
be
optionally substituted.
As used herein, the term "heterocyclic ring" or "heterocyclic ring system" is
intended to mean a substituted or unsubstituted member selected from the group
consisting of stable monocyclic ring having from 5-7 members in the ring
itself and
having from 1 to 4 hetero ring atoms selected from the group consisting of N,
O and
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S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in
the two
rings wherein at least one of the two rings has from 1 to 4 hetero atoms
selected
from N, O and S, including bicyclic ring structures wherein any of the
described
stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and
a
stable tricyclic heterocyclic ring structure having a total of from 10 to 16
atoms in
the three rings wherein at least one of the three rings has from 1 to 4 hetero
atoms
selected from the group consisting of N, O and S. Any nitrogen and sulfur
atoms
present in a heterocyclic ring of such a heterocyclic ring structure may be
oxidized.
Unless indicated otherwise the terms "heterocyclic ring" or "heterocyclic ring
system" include aromatic rings, as well as non-aromatic rings which can be
saturated, partially saturated or fully saturated non-aromatic rings. Also,
unless
indicated otherwise the term "heterocyclic ring system" includes ring
structures
wherein all of the rings contain at least one hetero atom as well as
structures having
less than all of the rings in the ring structure containing at least one
hetero atom, for
example bicyclic ring structures wherein one ring is a benzene ring and one of
the
rings has one or more hetero atoms are included within the term "heterocyclic
ring
systems" as well as bicyclic ring structures wherein each of the two rings has
at least
one hetero atom. Moreover, the ring structures described herein may be
attached to
one or more indicated pendant groups via any hetero atom or carbon atom which
results in a stable structure. Further, the term "substituted" means that one
or more
of the hydrogen atoms on the ring carbon atoms) or nitrogen atoms) of the each
of
the rings in the ring structures described herein may be replaced by one or
more of
the indicated substituents if such replacements) would result in a stable
compound.
Nitrogen atoms in a ring structure may be quaternized, but such compounds are
specifically indicated or are included within the term "a pharmaceutically
acceptable
salt" for a particular compound. When the total number of O and S atoms in a
single
heterocyclic ring is greater than 1, it is preferred that such atoms not be
adjacent to
one another. Preferably, there are no more that 1 O or S ring atoms in the
same ring
of a given heterocyclic ring structure.
Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical
order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-
carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-
dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl,
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imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-
indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,
pteridinyl,
purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl,
pryidooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,
pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-
thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
1,3,4-triazolyl
and xanthenyl. Preferred heterocyclic ring structures include, but are not
limited to,
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl,
indolyl,
benzimidazolyl, 1H-indazolyl, oxazolinyl, or isatinoyl. Also included are
fused ring
and spiro compounds containing, for example, the above heterocylic ring
structures.
As used herein the term "aromatic heterocyclic ring system" has essentially
the same definition as for the monocyclic and bicyclic ring systems except
that at
least one ring of the ring system is an aromatic heterocyclic ring or the
bicyclic ring
has an aromatic or non-aromatic heterocyclic ring fused to an aromatic
carbocyclic
ring structure.
The terms "halo" or "halogen" as used herein refer to Cl, Br, F or I
substituents. The term "haloalkyl", and the like, refer to an aliphatic carbon
radicals
having at least one hydrogen atom replaced by a Cl, Br, F or I atom, including
mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and
the like
as preferred radicals, for example.
The term "methylene" refers to -CH2-.
The term "pharmaceutically acceptable salts" includes salts of compounds
derived from the combination of a compound and an organic or inorganic acid.
These compounds are useful in both free base and salt form. In practice, the
use of
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the salt form amounts to use of the base form; both acid and base addition
salts are
within the scope of the present invention.
"Pharmaceutically acceptable acid addition salt" refers to salts retaining the
biological effectiveness and properties of the free bases and which are not
biologically or otherwise undesirable, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric
acid and
the like, and organic acids such as acetic acid, propionic acid, glycolic
acid, pyruvic
acid, oxalic acid, malefic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid,
citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
"Pharmaceutically acceptable base addition salts" include those derived from
inorganic bases such as sodium, potassium, lithium, ammonium, calcium,
magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
Particularly
preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
Salts derived from pharmaceutically acceptable organic nontoxic bases include
salts
of primary, secondary, and tertiary amines, substituted amines including
naturally
occurnng substituted amines, cyclic amines and basic ion exchange resins, such
as
isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine,
arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine,
ethylenediamine, glucosamine, methylglucamine, theobromine, purines,
piperizine,
piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly
preferred
organic nontoxic bases are isopropylamine, diethylamine, ethanolamine,
trimethamine, dicyclohexylamine, choline, and caffeine.
"Biological property" for the purposes herein means an in vivo effector or
antigenic function or activity that is directly or indirectly performed by a
compound
of this invention that are often shown by in vitro assays. Effector functions
include
receptor or ligand binding, any enzyme activity or enzyme modulatory activity,
any
carrier binding activity, any hormonal activity, any activity in promoting or
inhibiting adhesion of cells to an extracellular matrix or cell surface
molecules, or
any structural role. Antigenic functions include possession of an epitope or
antigenic site that is capable of reacting with antibodies raised against it.
In the compounds of this invention, carbon atoms bonded to four non-
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identical substituents are asymmetric. Accordingly, the compounds may exist as
diastereoisomers, enantiomers or mixtures thereof. The syntheses described
herein
may employ racemates, enantiomers or diastereomers as starting materials or
intermediates. Diastereomeric products resulting from such syntheses may be
separated by chromatographic or crystallization methods, or by other methods
known in the art. Likewise, enantiomeric product mixtures may be separated
using
the same techniques or by other methods known in the art. Each of the
asymmetric
carbon atoms, when present in the compounds of this invention, may be in one
of
two configurations (R or S) and both are within the scope of the present
invention.
Preferred Embodiments
In a preferred embodiment, the present invention provides a compound
according to the formula I:
A-Y-D-E-G-J-Z-L
wherein:
A is selected from:
(a) C,-C6 alkyl;
(b) C3-C$-cycloalkyl;
(c) phenyl, which is independently substituted with 0-2 R' subsituents;
(d) naphthyl, which is independently substituted with 0-2 R' subsituents;
and
(e) a monocyclic or fused bicyclic heterocyclic ring system having from
S to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R' subsituents;
R' is selected from:
halo, C,~alkyl, -CN, (CHZ)mNR2R3, SOzNR2R3, SOZR2, CF3, ORZ, and a 5-6
membered aromatic heterocyclic system containing from 1-4 heteroatoms
selected from N, O and S;
RZ and R3 are independently selected from the group consisting of
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H, C,~alkyl and Co~,alkylaryl,
m is an integer of 0-2;
Y is a member selected from the group consisting of
a direct link, -C(=O)-, -N(R4)-, -C(=O)-N(R4)-, -N(R4)-C(=O)-, -SOZ , -O-,
S -SOz-N(R4)- and N(R4)-SOz-;
R4 is selected from:
H, C,~alkyl and C~alkylaryl;.
D is absent or is a member selected from the group consisting of
(a) aryl, which is independently substituted with 0-2 R'a subsituents; and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from
5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, -and wherein the ring system may be
substituted with 0-2 R'a subsituents;
R'a is selected from:
Halo, C,~alkyl, -CN, -NOz, (CHz)mNRzaR3a, SOzNRzaR3a~ SOzRza~ CF3, ORza,
and a 5-6 membered aromatic heterocyclic ring containing from 1-4
heteroatoms selected from N, O and S;
Rza and R3a are independently selected from the group consisting of
H, C,~alkyl and C~alkylaryl;
E is a member selected from the group consisting of
-N~S)-C(=O)-~ -C(=O)-N~5)-~ -N~5)-C(=O)-N~6)-~ -SOz-N~5)-~
-N(RS)-SOz N(R6)- and N(RS)-SOz-N(R6)-C(=O)-;
RS and R6 are independently selected from:
H, C,_4alkyl, Co~alkylaryl, C~alkylheteroaryl, C,~alkylCOOH and
C,~alkylCOOC,~alkyl;
G is a member selected from the group consisting of:
a direct link, -CR'R8- and -CR'eRga-CR'aRBb-
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wherein R', R8, R'a, R$a, R'~ and Rgb are independently a member selected from
from
the group consisting of
hydrogen, C,~alkyl, C~alkyl-C3_8cycloalkyl, C~alkylaryl, -OR9,
-C°~alkylCOOR9, -C~,,alkylC(=O)NR9R'°, -N(R9)COR'°, -
N(R9)C(=O)R'°,
S -N(R9)SOZR'°, and common amino acid side chains;
R9 and R'° are independently selected from:
H, C,~alkyl and C°~alkylaryl;
J is a member selected from the group consisting of
Rm I R"
U'2
~n~ and
wherein the ring carbons or the second ring nitrogen of the amino ring
structure
and/or the ring carbons on the alkylene bridging groups attached to the amino
ring
structure may be independently substituted by a total of 0 to 4 R", R"a, R"b
and R"'
groups;
R", R"a, R"b and R"' are independently a member selected from the group
consisting of
hydrogen, -OH, -O-C,~,alkyl, -C,~alkyl, CZ_6alkenyl, CZ_balkynyl, C3_
8cycloalkyl, C°~alkyl-C3_8cycloalkyl, C°~alkylphenyl,
C°~alkylnaphthyl,
C°~alkylheterocyclic ring having from 1 to 4 hetero ring atoms
selected from
the group consisting of N, O and S, CHZCOOC,~alkyl,
CHZCOOC,~alkylphenyl and CHzCOOC,~alkylnaphthyl;
Z is a member selected from the group consisting of:
(a) aryl, which is independently substituted with 0-2 R'b subsituents;and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from
5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R'b subsituents;
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R'b is selected from:
halo, C,~alkyl, -CN, -NO2, NRZbR3b' SOz~26R36' SOzR2b' CF3' OR2b' O-CH2
CHz-ORzb, O-CHz-COORzb, N(Rzb)-CHZ CHZ ORzb, N(-CHZ CHz-ORzb)z,
N(Rzb)-C(=O)R36, N(Rzb)-SOz-R3b, and a 5-6 membered aromatic heterocyclic
ring containing from 1-4 heteroatoms selected from N, O and S;
Rzb and R36 are independently selected from the group consisting of
H, C,~alkyl and C~alkylaryl;
L is selected from:
H~ -CN~ C(-O)yzR~s~ (CHz)~~izR~3~ ~(-~12)~12R13' yzRis~ OR'z,
_I~TR'zC(-NR'z)NR'zRi3 ~d NR'zC(=NR'z)-R~s;
R'z and R" are independently selected from:
hydrogen, -OR", -NR'4R's, C,~alkyl, C~alkylaryl COOC,~,alkyl, and
COO-Co~alkylaryl;
R'4 and R's are independently selected from:
H and C,~alkyl; and
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In a further preferred embodiment, the present invention provides a
compound according to the formula I:
A-Y-D-E-G-J-Z-L
wherein:
A is selected from:
(a) phenyl, which is independently substituted with 0-2 R' subsituents;
and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from
5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
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selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R' subsituents;
R' is selected from:
halo, (CHz)",NRzR3, SOZNRZR' and SOZRZ;
RZ and R3 are independently selected from the group consisting of
H and C,~alkyl;
Y is a member selected from the group consisting of
a direct link, -C(=O)-, - SOZ- and -O-;
D is a member selected from the group consisting of
(a) phenyl, which is independently substituted with 0-2 R'a subsituents;
and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from
S to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R'a subsituents;
R'a is selected from:
Halo and C,~alkyl;
RZa and R'a are independently selected from the group consisting of
H, C,~alkyl, Co~alkylaryl;
E is a member selected from the group consisting of
-N(RS)-C(=O)- and -C(=O)-N(RS)-;
RS and R6 are independently selected from:
H, C,~alkyl, C~alkylaryl and Co~alkylheteroaryl;
G is a member selected from the group consisting of
a direct link, -CR'Rg- and -CR'aRBa-CR'aR86-
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wherein R', R8, R'a, Rga, R'~ and R86 are independently a member selected from
from
the group consisting of
hydrogen, C,~alkyl, C°~alkyl-C3_8cycloalkyl, Co~alkylaryl, -OR9,
-C°~alkylCOOR9, -C°~alkylC(=O) NR9R'°, -C~alkylC(=O)NR9-
CHZ-CHz-O-
S R'°, -Co-aalkYlC(=O)NR9(-CHZ-CHZ-O-R'°_)i, -
N(R9)COR'°, -N(R9)C(=O)R'o,
-N(R9)SOZR'°, and common amino acid side chains;
R9 and R'° are independently selected from:
H and C,~,alkyl, wherein the NR9R'° group of R', R8, R's, RBa, R'~ and
R8b is
optionally cyclized to form a 5-8 membered heterocyclic group;
J is a member selected from the group consisting of:
Ro I R"
~~~ 1_2
~~ 1-2
and
wherein the ring carbons or the second ring nitrogen of the amino ring
structure may
be substituted by a total of 0 to 2 R" and R"~ groups;
R", R"e, R"b and R"~ are independently a member selected from the group
consisting of
hydrogen, -OH, -O-C,~alkyl, -C,~alkyl, Cz_balkenyl, C~alkylaryl, and a
C°~,alkylheterocyclic ring having from 1 to 4 hetero ring atoms
selected from
the group consisting of N, O and S;
Z is a member selected from the group consisting of
(a) phenyl, which is independently substituted with 0-2 R'b subsituents;
(b) an aromatic heterocyclic ring having from 5 to 10 ring atoms,
wherein 1-4 ring atoms are selected from N, O and S, and wherein the
ring may be subsituted independently by from 0-2 R'b subsituents;
and
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(c) a fused aromatic bicyclic heterocyclic ring system having from S to
ring atoms, wherein 1-4 ring atoms of the ring system are selected
from N, O and S, wherein the bicyclic ring system may be substituted
with 0-2 R'b subsituents;
5 R'b is selected from:
halo, C,.~alkyl, OH, OBn, O-CHz-CHz-OH, O-CHZ CHz OCH3,
O-CHz COOH, O-CHZ C(=O)-O-CH3, NHz, NH-CHz-CHz-O-CH3,
NH-C(=O)-O-CH3, and NH-SOz-CH3;
L is selected from:
10 H~ C(-O)yzRm~ (CHz)n~tzRt3 ~d C(=NR'z)NR'zR~3~
R'z and R'3 are independently selected from:
hydrogen and C,~alkyl;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In a further preferred embodiment, the present invention provides a
compound according to formula I:
A-D-E-G-J-Z-L
wherein
A is a member selected from the group consisting of
OZNHz 02NHMe OZNHBu(t) OZMe
HZNHz HZNMez
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D is a member selected from the group consisting of
/ \ /- / \ / \
F
F F F
/ \ / \ / \
F a F
S E is a member selected from the group consisting of::
-C(=O)-NH-, -C(=O)-N(-CH,)-, C(=O)-N(-Bn)-, -NH-C(=O)-, -N(-CH3)-
C(=O)- and -N(-Bn)C(=O)-;
G is a member selected from the group consisting of
a direct link, -CH-(-NHZ)-CHz , -CH-(-NH(C(=O)-CH3))-CHz-,
-CH-(-NH(C(=O)-Ph))-CHZ , -CH-(C(=O)-OR8)-, -CH(-R')-,
-CHZ-CH(C(=O)-OR8)-, and -CHZ CH(C(=O)-N(-R8, -R8))-;
R' is a member selected from the group consisting of
H, phenyl, Bn, -O-loweralkyl and cycohexyl;
R$ is a member selected from the group consisting of
H, C,_6alkyl, -O-loweralkyl and C3_bcycloalkyl;
J is a member selected from the group consisting of
R1 t c
~~ 1_2 ~~ 1_2
r.~ and
wherein the second ring nitrogen of the amino ring structure may be
substituted by a
R"~ group;
R"~ is a member selected from the group consisting of
H, methyl, phenyl and benzyl; and
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Z and L taken together are a member selected from the group consisting of:
OCHZCOOH OH F OMe OCHzCH20H OCI-hCHZOMe
\ \
I/ I/ I/ I/ I/ I/ I/
Hz NH Hz NH Hz NH Hz NH Hz NH Hz NH Hz NH
CHzCOOMe NHCH1COOH N(CHzCH20Mey~ NH(CHZCCHZOMe)
\ \
I \ I / I / I / ~ / F I / OH
Hz NH Hz NH
Hz NH Hz NH Hz NH Hz NH
\ \ \ \ F
\ \ \ I I I I
/ NH /~O /~S /
I / I / I \
N~ ~ -N -N -N
Hz O HZN HzN HZN HzN Hz NH
OH N~ OH NHz
\ \
/ \ I / I / I / g I / NH
\ ~~H O
N~ I / N/ N ~NHz ~Nf'~z
Hz 'O N~ HzN HZN
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
The following non-limiting tables illustrate representative compounds of the
present invention:
15
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Table 1
Ib'~
R~~, R ~~ R~h~
R
H H H H
Me Me H OH
I F H
I -0H F
~:
OH
Table la
OyNHy ... ...
H
1b'
Form
R», R~r Rio. Rye.
H H H H
Me Me H OH
\ \
I / I ~ F H
I / I ~ -OH F
H~
H
r mma a
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Table 1b
OpNHp
H
1b'
Formula
Rtr Rtt' Rtb, Rtb-
H H H H
Me Me H OH
F H
-OH F
CH=
OH
Table lc
Rttc Rtt
O pNH p N
Rtb.
N ~N
~ H
Rtb'
Formula IIc
HN NHy
Rtt Rttc Rtt~ Rtb'
H H H H
Me Me H OH
Me F H
Me ~ / -OH F
OH
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Table 1d
OpNH2
H
Formula
1b'
Rtt, Rtt. Rte, Rtb.
H H H H
Me Me H OH
Me F H
Me I / -OH F
OH
Table 1 a
Rttc Rtt
OzNHz N Rt°~
N
H I' /~
V 'otb'
Formula IIe
Rtt Rtic Rtb~ Rtb'
H H H H
Me Me H OH
F H
-OH F
CHz
OH
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Table 2
OpNH2 Rtt' Rtu
N
H Rtr
NH
HpN
Formula III
Rtt' Rtt' Rtn
H H H
Me Me H
\ \
/ F
\
-OH
CHi
OH
Table 2a
Rtr Rtt.
OyNH2 Rto
N ~~~\~ ~~ \
H
[JH
Formula IIIa HZN NN
R ~ R ~ Rto
H H H
Me Me H
Me F
Me ~ / -OH
OH
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Table 2b
H H H
Me ~ Me H
\ \
F
-OH
CHZ
OH
Table 2c
OZNHZ ,b
N ~~
H
NH
Formula IIIc HZN N
R »' R"c R , b
H H H
Me Me H
\ Me F
Me ~ / -OH
OH
Formula IIIb
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Table 2d
R~~
R~~~
OzNHz HN Rib
N- ''-N
H ~ ,
~H
Formula llld HzN NN
Rw Rir Rib
H H H
Me Me H
Me F
Me / -O H
OH
Table 2e
OZNH2
H
F~rmu
R»' Rttc R7u
H H H
Me Me H
\ F
/ ~ /
\
-OH
CHZ
OH
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Table 3
OzNHz Rtr Rip
N
H
R" /
HzN N
Formula IV
Rti' R»~ Rin
H H H
Me Me H
\ I \ F
I \
-OH
CH=
OH
Table 3a
OzNH2
H
Form
R »~ Rat
H H H
Me ~ Me H
F
-OH
CHz
OH
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Table 3b
R "'
O zNH z Rib
H N
R~~~ /
Formula IVb HZN N
R ~~ R ~ R
H H H
Me Me H
F
I \
-OH
CHZ
OH
Table 3c
OpNH2
H
For
R»' R»c Rtb
H H H
Me Me H
\ \
F
-OH
CH2
OH
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Table 3d
OzNHp
H
Formula m a
Rtt Rttc Rtb
H H H
Me Me H
\ F
/ ~ /
\
-OH
CHz
OH
Table 3e
Rttc Rtt
OZNH2 ~~ Rto
H N
Formula IVe HZN ~N
Rtt Rttc Rtb
H H H
Me Me H
\ \
F
-OH
CHZ
OH
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Table 4
O2NHZ R~r Rib
N
H R »,
Formula V HZN N
R , R . R
H H H
Me Me H
F
/ ~ /
-OH
CHy
H
Table 4a
OpNHz
H
Formula
R», R . Rtb
H H H
Me Me H
\ \
/ F
-OH
CHz
OH
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Table 4b
OZNHp
H
Formula ..,
_R~r
H H H
Me Me H
/ F
-OH
CHZ
OH
Table 4c
Rttc R»
OzNHZ
N' V-N \
H
Formula VC HZN N
R» R»c RW
H H H
Me Me H
F
-OH
CH=
OH
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Table 4d
R"
I
O pNH p N R,o
R~~
N
Formula Vd
HzN
R" R"c R,o
H H H
Me Me H
\ \
I / I F
-OH
CHZ
OH
Table 4e
~,lc R"
OzNHz R,t
H N
Formula Ve HzN 1
Rtt R"c R1b -
H H H
Me Me H
\ \
F
\
-OH
CH=
OH
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Table 5
OpNHz Rtt' Rtb
H Rtt I N
Formula VI HZN N
Rtt' Rtt ~ Rtb
H H H
Me Me H
\ \
I / I / F
I I / -OH
CHz
OH
Table Sa
OzNH2
Formul,
R», R _ R
H H H
Me ~ Me H
F
/ -OH
CHz
OH
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-37-
Table Sb
R~~
OpNHy R1b
N
H Rt1'
H2N N
Formula VIb
R~~, R». Rtb
H H H
Me Me H
\ \
F
\
-OH
CHZ
OH
Table Sc
OpNH2
H
Formula
R» RW Rib
H H H
Me Me H
\ \
F
I \
-OH
CHZ
OH
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-38-
Table Sd
OzNHp
H
Forr
R11 Rllc R1b
H H H
Me Me H
\ F
/ ~ /
-OH
CHZ
H
Table Se
R~lc
OzNH2 N
N
H
Formula ' VIe HzN I N
Rt~c
H H H
Me Me H
\ \
F
-OH
CHZ
OH
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-39-
Table 6
OpNH2 R»" Rtb
N
H
R~~
Formula VII
N
R»' Rw RW
H H H
Me Me H
F
/ ~ /
-OH
CHZ
OH
Table 6a
OzNH2
H
FOrml
R»' Rto Rat
H H H
Me ~ Me H
\ \
F
I \
/ ~ -OH
CHz
OH
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-40-
Table 6b
OpNHZ
Formula
R»' R~r Rat
H H H
Me Me H
\ I\ F
I/
I\
-OH
I
CHZ
OH
Table 6c
OpNHy
H
Four
R11 Rllc Rlb..
H H H
Me Me H
\ \
I / F
I / I ~ -off
CHZ
OH
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-41 -
Table 6d
R11 Rl~c Rib
H H H
Me Me H
\ I \ F
I \
-OH
CHZ
OH
Table 6e
OpNHp
H
Forma
Rllc R1b
H H H
Me Me H
\ \
F
I \
-OH
CH=
OH
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-42-
Table 7
A D A D
OZNHz HZN Mez F
CI
OpNHMe
F
OzNHf3u(t)
CI
OZMe F
F
HzNH F
HZ I
N
F
HZNHMe Hz
N/
F
".~a~~.~ ...~ H2
CA 02374788 2001-11-20
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-43-
Table 7a
!H2
A D A D
OZN Hz HZN Mez F
CI
OzNHMe
F
OZNHBu(t)
N/ \
CI
O2Me F
F
HZNHz F
N N
Hz i ~ I-~
F
HZNHMe H
z
F
CA 02374788 2001-11-20
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-44-
Table 7c
IH2
A D A D
OZNHp HZNMe2 F
CI
OZNHMe
F
OZNHBu(t)
CI
OZMe F
F
HZNH F
Hz I
F
HZNHMe HZ
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
- 45 -
Table 7c
IH2
A D A D
OzNHz HZNMe2 F
CI
OZNHMe
/
F
O2NHBu(t)
/
CI
OZMe F
F
HpNHz F
HZ
F
HzNHMe H2
/ ~ / \ N~
F N
CA 02374788 2001-11-20
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-46-
Table 7d
A D A D
OzNH2 HZNMe2 F
CI
OpNHMe
/
F
OZNHBu(t)
/
CI
OzMe F
F
HpNH F
HZ /
N
F
HZNHMe / ~ Hz / \
I ~ ~ ~N
F
Formula VIBd H2
CA 02374788 2001-11-20
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-47-
Table 7e
H2
A D A D
OZNHz HZNMez F
CI
OZNHMe
F
OZNHBu(t)
CI
OZMe F
F
HZNHz F
Hz I
F
HZNHMe Hz
F
CA 02374788 2001-11-20
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-48-
Table 8
H
Formula IX
A D A D
OZNHz HZN Mey F
CI
OzNHMe
F
02NHt3u(t)
CI
OZMe F
F
HZNHZ F
HZ ~
F
HpNHMe H2
F
wherein R'b is a member selected from the group consisting of H, F, -OH,
CA 02374788 2001-11-20
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-49-
Br, Cl, -NH2, -O-CHZ-O-Ph and -O-CHz-CHZ-O-CH,,
Table 8a
H
Formula IXa
A D A D
02NHz HZNMez F
CI
OpNHMe
F
OZNHt3u(t)
CI
OZMe F
F
HZNHz F
Hz ~
F
HzNHMe H
z
N
F
wherein R'b is a member selected from the group consisting of H, F, -OH,
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-SO-
Br, Cl, -NHz, -O-CHz-O-Ph and -O-CHZ-CHz-O-CH3,
Table 8b
OZNH2 .,
Formula IXb
A D A D
OzNH2 HZN Mez F
CI
OzNHMe
F
OZNHBu(t)
CI
02Me F
F
HzNHZ F
Hz ~
N
F
HZNHMe Hz
F
wherein R'b is a member selected from the group consisting of H, F, -OH,
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
- S1 -
Br, Cl, -NH2, -O-CHZ-O-Ph and -O-CHZ-CHZ-O-CH3,
Table 8c
H
Formula IXc
A D A D
OpN Hy HZN Mey F
CI
OzNHMe
F
OzNHBu(t)
CI
OZMe F
F
HZNH F
HZ
F
HZNHMe Hz
F
wherein R'b is a member selected from the group consisting of H, F, -OH,
CA 02374788 2001-11-20
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-52-
Br, Cl, -NH2, -O-CHZ-O-Ph and -O-CHz-CHZ-O-CH3,
Table 8d
H
A D A D
OZNHZ HZNMep F
CI
OZNHMe
F
OzNHBu(t)
CI
OZMe F
F
HzNH2 F
I ~ ~ ~ HZ I
F
HZNHMe H:
F
wherein R'b is a member selected from the group consisting of H, F, -OH,
CA 02374788 2001-11-20
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-53-
Br, Cl, -NHZ, -O-CHz-O-Ph and -O-CHZ-CHZ-O-CH3,
Table 8e
OzNHz
~A~ ~D~
H
Formula IXe
A D A D
OZN HZ HZN Me2 F
CI
OZNHMe
F
OzNHl3u(t)
CI
OzMe F
F
HyNH2 F
Hz
F
HZNHMe H2
N/ ~ N
F
wherein R'b is a member selected from the group consisting of H, F, -OH,
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-54-
Br, Cl, -NHz, -O-CHz-O-Ph and -O-CHZ-CHZ-O-CH3,
Table 9
A D A D
OZNHz HZN Me2 F
CI
O2NHMe
F
OZNHBu(t)
CI
OZMe F
F
HZNHz F
N N
HZ I
F
HZNHMe Hz
F
Formula X
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-55-
Table 9a
A D A D
OZNHz HZNMez F
CI
OZNHMe
F
OzNHBu(t)
CI
OzMe F
F
HzNHz F
Hz
N
F
HZNHMe Hz
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-56-
Table 9b
Formula Xb
A D A D
OZNHZ HZNMez F
CI
OzNHMe
F
OZNHBu(t)
CI
OZMe F
F
HzNHz F
Hz ~
F
HpNHMe H2
N
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-57-
Table 9c
02NH2
f
Formt
A D A D
OzNH2 HZNMez F
CI
OpNHMe
F
OZNHt3u(t)
CI
OZMe F
F
HzNH2 F
Hz
F
HZNHMe ~ ~ Hz N
N
F
CA 02374788 2001-11-20
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-58-
Table 9d
A D A D
OZNHz HZNMe2 F
CI
OZNHMe
F
OZNHBu(t)
CI
OZMe F
F
HzNH2 F
HZ ~
F
HZNHMe Ha
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-59-
Table 9e
OzNH2
Fore
A D A D
OZNH2 HZNMep F
CI
OyNHMe
F
OyNHBu(t)
CI
OzMe F
F
HpNH2 F
N N
HZ I ~ I-~
F
HZNHMe Hs
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-60-
Table 10
OZNHZ
Formul
A D A D
OzN HZ HZN Mez F
CI
OzNHMe
F
OZNHBu(t)
CI
OzMe F
F
HZNHz F
N N
HZ ~
F
HZNHMe H2
N
F
CA 02374788 2001-11-20
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-61-
Table 10a
A D A D
OyNHz H2NMez F
CI
OZNHMe
F
OzNHBu(Q
CI
OzMe F
F
HZNHz F
N N
Hz
F
HyNHMe Hz
F
CA 02374788 2001-11-20
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-62-
Table lOb
A D A D
OyNHp HzNMep F
CI
O=NHMe
F
OZNHBu(t)
CI
OZMe F
F
HZNH F
HZ
F
HZNHMe H2
N
F
rormuia ~m
CA 02374788 2001-11-20
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-63-
Table lOc
H
N
A D A D
OyN Hz HZN Mez F
CI
OpNHMe
F
OZNHBu(t)
CI
OyMe F
F
~NHz F
Hz I
F
HzNHMe Hz
F
CA 02374788 2001-11-20
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-64-
Table lOd
OzNHz
H
Formula
A D A D
OzNH2 HZNMe2 F
CI
OzNHMe
F
OzNHBu(t)
CI '
OzMe F
F
HyNHy F
HZ
F
HzNHMe Hz
F
CA 02374788 2001-11-20
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-65-
Table 10e
A D A D
OZN Hp H=N Mez F
CI
OZNHMe
F
OZNHBu(t)
CI
OzMe F
F
HZNHz F
Hz ~ ~ ~-~'
F
HZNHMe Hz
N
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-66-
Table 11
a o a o
OZNHz HZNMe2 F
CI
OZNHMe
F
OZNHBU(t)
N
CI
OpMe F
F
FiiNHp F
N N
HZ
F
HZNHMe Hs
I ~ / \ N~
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-67-
Table 11 a
A D A D
OZNHz HZNMez F
CI
OZNHMe
F
OzNHt3u(t)
CI
OpMe F
F
F
HZNHz
N N
HZ
F
HZNHMe Hs
N
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-68-
Table 11 b
A D A D
OZNHz HzNMez F
CI
OyNHMe
F
OZNHBu(t)
CI
OZMe F
F
HZNHz F
Hz
F
HZNHMe Hz
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-69-
Table 11 c
A D A D
OzNHZ H2N Mez F
CI
OzNHMe
F
OZNHBu(t)
CI
02Me F
F
HZNHp F
N N
HZ I
F
H2NHMe HZ
F N
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-70-
Table 11 d
OzNHz
Formula
A D A D
OZNHp HZN MeZ F
CI
OZNHMe
F
OzNHBu(t)
CI
OzMe F
F
HZNH F
N N
HZ
F
H NHMe
HZ N
N
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-71-
Table 11 a
OzNH2
\A/ \D/ NH
Formula X
A D A D
OZN HZ HzN Mez F
CI
OZNHMe
F
OZNHBu(t)
CI
OZMe F
F
HyNH2 F
HZ
N
F
HZNHMe H2
F
CA 02374788 2001-11-20
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-72-
Table 12
)H
OzNHz
H
Formula XIII
A D A D
OZN H2 HzN Me2 F
CI
OzNHMe
F
OZNHBu(t)
CI
OpMe F
F
HpNH2 F
HZ
F
HyNHMe ~ ~ HZ
F
CA 02374788 2001-11-20
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-73-
Table 12a
A D A D
OZNHz HZN Me2 F
CI
OzNHMe
F
OzNHBu(t)
CI
OZMe F
F
I-hNH F
HZ I
N
F
HZNHMe H2
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-74-
Table 12b
OpNHz
Formula XIII
A D A D
OZNHZ HZN Me2 F
CI
02NHMe
F
OZNHt3u(t)
CI
OzMe F
F
HzNHz F
N N
Hz I
F
HzNHMe ~ ~ Hz
N
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-75-
Table 12c
OzNH2
\A~ \p~ NH
Formula
A D A D
OZNHz HZN Mez F
CI
OZNHMe
F
OZNHBu(t)
CI
OZMe F
F
HzNHz F
Hz ~
N
F
HyNHMe Hz
F
CA 02374788 2001-11-20
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-76-
Table 12d
A D A D
OzNHz HZNMez F
CI
OzNHMe
F
OZNHBu(t)
CI
OZMe F
F
~NHz F
Hz ~
F
HZNHMe Hz
F
CA 02374788 2001-11-20
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_77_
Table 12e
A D A D
OzNHZ HZNMez F
CI
OZNHMe
F
OZNHBu(t)
CI
OZMe F
F
HZNHZ F
HZ ~
F
HZNHMe ~ ~ Hs
N
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
_78_
Table 13
H2
Formula XN
A D A D
O2NHz HZNMeZ F
/ \ / \ / \ / \
C
OzNHMe
/ \ / \ / \ / \
F
OzNHl3u(t)
/ \ / \ / \ / \
ci
OpMe F
/ \ / \ / \ /-\
F
HzNH2 F
/ \ / \ NhZ / \ / \
F
HZN H Me H2
/ \ / ~ / \
F
CA 02374788 2001-11-20
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-79-
Table 13a
Formula XIVa
A D A D
OZNHZ HZNMe2 F
/ \ / \ / \ / \
C
OyN H Me
/ \ / \ / \ / \
F
OZNHBu(t)
/ \ / \ / \ / \
CI
OzMe F
/ \ / \ / \ / \
F
HZNHZ F
/ \ / \ Nnz / \ / \
F
HZNHMe
HZ
/ \ / \ / \
F
CA 02374788 2001-11-20
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-80-
Table 13b
NH2
Formula XIVb
A D A D
02NHz HZNMe2 F
/ \ / \ / \ / \
C
OZNHMe
/ \ / \ / \ / \
F
OZNHBu(t)
/ \ / \ / \
/ \
CI
OZMe F
/ \ / \ / \ /-\
F
HzNHy F
/ \ / ~ Nh2 / \
F
HZNH Me H2
/ \ / ~ / \
F
CA 02374788 2001-11-20
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-81-
Table 13c
NH2
Formula XIVc
A D A D
OZNHZ HZNMeZ F
C
O2N H Me
F
OzNHBu(t)
CI
OZMe F
F '
HzNH F
Nhy /
F
H NHMe
H2
F
CA 02374788 2001-11-20
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-82-
Table 14
H2
Formula XV
A D A D
OzNHp HzNMez F
/ \ / \ / \ / \
C
OZNHMe
/ \ / \ / \ / \
F
OZNHt3u(t)
/ \ / \ / \
/ \
CI
OZMe F
/ \ / \ / \ /-\
F
HzNH F
/ \ / \ Nhz / \ /-\
F
HzNHMe
H2
/ \ / \ / \
F
CA 02374788 2001-11-20
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-83-
Table 14a
Formula XVa
A D A D
OzNHz HZNMez F
/ \ / \ / \ / \
CI
OZNHMe
/ \ / \ / \ / \
F
OzNHBu(t)
/ \ / \ / \
/ \
CI
OZMe F
/ \ / \ / \ /-\
F
HzNHz F
/ \ / \ NhZ / \ / \
F
HzNHMe Hz
/ \ / ~ / \
F
CA 02374788 2001-11-20
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- 84 -
Table 14b
JH2
Formula XVb
A D A D
OZNHZ HZNMez F
/ \ / \ / \ / \
CI
OzN H Me
/ \ / \ / \ / \
F
OZNHBu(t)
/ \ / \ / \ / \
CI
OZMe F
/ \ / \ / \ / \
F
I-hNH2 F
/ \ / \ Nh2 / \ / \
F
HZNHMe Hz
/ \ / ~ / \
F
CA 02374788 2001-11-20
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-85-
Table 14c
Formula XVc
A D A D
02N HZ HZN Mey F
/ \ / \ / \ / \
C
OZNHMe
/ \ / ~ / \ / \
F
OZNHBu(t)
/ \ / \ / \
/ \
ci
OZMe F
/ \ / \ / \
F
HZNHz F
/ \ / \ Nh2 / \ /-\
F
HzNHMe
Hz
/ \ / ~ / \
F
CA 02374788 2001-11-20
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-86-
Table 15
A D A D
OZNHZ H2NMez F
/ \ / \ / \ / \
CI
OyNHMe
/ \ / \ / \ / \
F
OpNHBu(t)
/ \ / \ / \
/ \
CI
OzMe F
/ \ / \ / \
F
HZNHZ F
/ \ / \ Nh2 / \
F
HZNHMe Hz
/ \ / \ / \
F
Formula XVI
CA 02374788 2001-11-20
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_87_
Table 15a
!H2
Formula XVIa
A D A D
OzNHZ HzNMe2 F
/ ~ /
C
OyNHMe
/ ~ /
F
OZNHBu(t)
/ ~ /
CI
OZMe F
/ ~ / \ / ~ / \
F
HzNH F
/ ~ / ~ Nnz / ~ / \
F
H2N H Me H2
/ ~ /
F N
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
_8g_
Table 1 Sb
dH2
Formula XVIb
A D A D
OZNHZ HzNMe2 F
C
SOZNHMe
F
OZNHBu(t)
CI
OZMe F
F
HpNH F
Nh2 /
F
HzNHMe
H2
/
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-89-
Table 1 Sc
H2
OH
Formula XVIc
A D A D
OzNHz HpNMez F
/ ~ /
C
O2NHMe
/ ~ /
F
OzNHBu(t)
/
/
CI
OZMe F
/ ~ /
F
HZNHz F
/ ~ / ~ Nnz / ~ / \
F
HZNHMe H2
/
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-90-
Table 16
Formula XVII
A D A D
OzNH2 HzNMez F
/ ~ /
G
OzNHMe
/ ~ /
F
OZNHBu(t)
/ ~ /
G
O=Me F
% ~ /-\
F
HpNHy F
Nhz / ~ /-\
F
zNHMe
Hz
F/ ~ /
N
CA 02374788 2001-11-20
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-91 -
Table 16a
H2
Formula XVIIa
A D A D
OZNHz HZNMe2 F
/ \ / \ / \ / \
C
OzNHMe
/ \ / \ / \ / \
F
OzNHl3u(t)
/ \ / \ / \ / \
CI
OzMe F
/ \ / \ / \ /-\
F
HZNHZ F
/ \ / \ Nhz / \ /-\
F
HzNH Me H2
/ \ / ~ / \
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-92-
Table 16b
Formula XVIIb
A D A D
OZNHz HzNMez F
/ \ / \ / \ / \
C
OZN HMe
/ \ / \ / \ / \
F
OZNHBu(t)
/ \ / \ / \ / \
CI
OZMe F
/ \ / \ / \ /-\
F
HzNH F
/ \ / \ Nhz / \ /-\
F
H2NHMe Hz
/ \ / ~ / \
F
CA 02374788 2001-11-20
WO 00/71515 PCT/US00/14193
-93-
Table 16c
JH2
A D A D
OZNHz HZNMez F
C
OZNHMe
F
O2NHt3u(t)
/
CI
OZMe F
-\
F
HzNHz F
Nhz / ~ ~ \
F
HzNHMe
Hz
/
F
Formula XVIIc
CA 02374788 2001-11-20
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-94-
Table 17
1 b"
R7 ~ R11 ~ R1b' Rib"
H H H H
Me H H OH
\ F H
/ -OH F
CHz
OH
OH
\
/ OH OH
CHZ
H _ OMe
I \ / -NH2 H
/ CHz
Formula XVIII
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Table 17a
Formula XVBIa
R7 ~ R11 ~ R1b' ~ R1b"
H H H H
Me H H OH
\ F H
(/ ~/
/ -OH F
CHz
OH
OH
/ OH OH
CHZ
Hz- OMe
\
\ / -NH2 H
/ CHz
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Table 17b
1b"
R7 ~ R11 ~ R1b' ~ R1b"
H H H H
Me H H OH
\ \
F H
/ -OH F
CHz
OH
OH
\
/ OH OH
CHZ
H_ OMe
z \
I \ / -NH2 H
/ CHz
Formula XVIIIb
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Table 17c
R7 ~ R11 ~ R1b' ~ R1b~
H H H H
Me H H OH
\ \
F H
/ -OH F
CHZ
OH
OH
/ OH OH
CHZ
H OMe
\ / -NH2 H
I CHz
/
Formula XVIIIc
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Table 18
R1 R2 R1 R2
\ \
H H I/ I/
H=
H
OH
Me H I /
H=
Hi. \ OMe
I\ I/ I\ I/
/
H~
Table 18a
I
02NH2
NH
/
NHS
Formula XIXa
- R7 Rltc R7 Rllc
\ \
" H I I/
CH=
OH
H
Me H I /
CH=
H=. \ OMe
\ / \ /
/ /
CHi
t' ormula XIX '
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Table 18b
R"
02NH2
N ~ \ ~ /NH
H
R~
Formula XIXb
R~ R~ ~ R~ R~ ~
\ \
H H I / I /
CHy
OH
H
Me H I /
CH2
HZ_ \ OMe
I ~ I / I ~ /
CHZ
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Table 18c
R"°
02NHz
N ~ ~ ~ NH
H /
R~
Formula XIXc NH2
R7 R "c R7 R "c
w
H H I / I /
CHZ
OH
H
Me H I /
CHz
HZ_ OMe
\ / I \ /
/ / CHZ
1~
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Table 19
OZNH2 R~~
H I,,
NH2
Formula XX
R~ R~~ R7 R~~
H H I / I /
CHZ
OH
H
Me H ( /
CHZ
H=_ OMe
I\ I/ I\ I/
/ / CHz
Table 19a
Rl~c
OZNH2 N
'I
N N
~ H
R~
NH2
Formula XXa
R7 R~~c R~ Rllc
H H I / I /
CHx
OH
H
Me H I /
CH=
Hz_ \ OMe
I\ / I\ I/
/ / CHz
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Table 19b
R~~
OpNHz ~ \
N~ \ I / N
H ~I,,,
~z
Formula XXb
R~ R~~ R~ R~~
\
H H I / I /
CHZ
OH
H
Me H I /
CHZ
HZ_ OMe
I\ I/ I\ /
/ /
H=
Table 19c
Rllc
OZNHz N
N ~ ~ I
H
R
NHz
Formula XXc
R7 R~tc R7 R~lc
H H I I /
/ CHZ
OH
H
Me H I /
CHZ
Hx_ Me
I\ / I\ /
/ /
CH=
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Table 20
OZNHz Rtt
N
R~
Formula XXI H2N
R~ Rtt R~ Rtt
\ \
H H I I /
/ CHZ
OH
H
Me H I /
CHz
HZ_ \ OMe
I\ I/ I\ I/
/ /
CHz
Table 21
OZNHp Rtt
N iH
H ~ ~ ~ ~N
R
HzN
Formula XXII
R~ Rtt R~ Rtt
H H I I /
/ CH=
OH
H
Me H I /
CH=
Hz_ \ OMa
I\ I/ I\ I/
/ /
CHZ
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Table 20a
R "~
OZNHz I
/ O~
N
\ / \ / H
R~
NHy
Formula XXIa
R7 R"c R7 R,tc
\
H H I I /
/ CHI
OH
H
Me H I /
CHZ
Hx_ \ Me
I \ I / I \ I /
/ /
CHz
Table 21a
R "c
02NH2 I H
/ N\
\ / \ / H
R~
NHZ
Formula XXIIa
R7 R"c R7 R"c
H H I I /
/ CH=
OH
H
Me H I /
CH=
Hz_ \ a
I\ I/ I\ I/
CHZ
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Table 20b
OzNH2
Rtt
H
R~
Formula XXIb HZN
R~ Rtt R~ Rtt
H H I I /
/ CH2
OH
H
,",e H I /
CH=
Hz. \ Me
I\ I/ I\ I/
/ /
CHZ
Table 21b
H
OzNHz Rtt ~ / N\
N \ I /N
H NHZ
Formula XXIIb
R~ Rtt R~ Rtt
H
H I I/
/ CHI
OH
H
Me H I /
CHZ
HZ_ \ OMe
I\ I/ I\ I/
/ /
CHz
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Table 20c "_
OZNHZ
H
Formula
R 7 R"c R 7 R"c
\
H H I I /
/ CHZ
OH
H
Me H I /
CHZ
Hs_ \ OMe
\ I/ I\ I/
/ /
CHy
Table 21c
R"~
OzNHy N H
N~
N
H N \
R~ NH2
Formula XXIIc
R7 R"c R7 R"c
\ \
H H I I /
/ CHy
OH
H
Me H I /
CHZ
Hz_ \ OMe
I\ I/ I\ I/
/ /
CHz
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Table 22
OzNHz
H
Form
R~ R~~ R~ R~~
\
H H I I /
/ CHz
OH
H
Me H ~ /
CHz
Hz_ \ OMe
/ ~ /
CHz
Table 23
OpNHp R~~
H ~ ~H
R ~ ~ NiN
Formula XXIV
R~ R~~ R~ R~~
\
H H I / I /
CHz
OH
H
Me H I /
CHz
H=_ \ OMe
I\ / I\ I/
/ /
~z
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Table 22a
02NH2
Formu
R7 Rt~c R7 R~lc
H H I I /
/ CHx
OH
H
Me H I /
CHx
Hx_ \ OMe
I\ I/ I\ /
/ /
CHx
Table 23 a
R~~°
O2NH2
H ~ ~ ~ iH
R Ni N
Formula XXIVa
R~ R~~ R7 R11 c
\
H H I I /
/ CHx
OH
H
Me H I /
CHx
Hx_ \ OMe
I/ I/ I/ I/
CHx
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Table 22b
OzNH2
R~~
R~
/ N
HZN
Formula XXIIIb
R~ Rat R~ R~~
\ \
H H I I/
CHx
OH
H
H I/
CHI
Hz_ \ OMe
\ / \ I/
/ /
CHz
Table 23b
OZNHp O
R~~
iH
NON
Formula XXIVb
R~ R~~ R~ R~~
H H I I /
/ CHz
OH
H
Me H I /
CHx
Hz_ \ OMe
\ / I\ I/
/ /
~z
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Table 22c
O yN Hz
H
Formula
R7 Rttc R7 Rttc
H H I I /
/ CHx
OH
H
Me H I /
CHp
H=_ OMe
I\ / I\ I/
/ /
CHp
Table 23c
R7 Rttc R7 Rttc
H H I / I /
CHi
OH
H
Me H I /
CHZ
HZ_ OMe
I\ I/ I\ I/
/ /
MHz
Formula XXIVc
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Table 24
R~~
OZNHz
H R~
N NHz
Formula XXV
R~ R~~ R7 R~~
\
H H I I /
/ CHz
OH
H
Me H I /
CHZ
HZ. \ OMe
I\ I/ I\ I/
/ /
CHZ
Table 24a
R~~
OpNHp N
H
R~
N NH2
Formula XXVa
R~ R~~ R~ Rllc
H H I I /
/ CHx
OH
H
Me H I /
CHz
I \ I / I \_ I % Me
/ /
CHi
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Table 24b
02NHz
H
N NH2
Formula XXVb
\
H H I I /
/ CHz
OH
H
Me H I /
CHz
HZ_ Me
/ I/ I\ I/
/
CHx
Table 24c .._
OZNH2
H
NHp
Formula XXVc
R7 R~lc R7 Rllc
\
H H I
I/
/ CH2
OH
H
Me H I
CHx
Hz_ \ OMe
\ I/ I\ I/
/ /
CHz
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Table 29c
Rtt° Rtt
OzNH2 _ N~~ H
N
H N I ~NH2
N
Formula XXXc
Rtt Rtt~ Rtt Rtt
\
H H I I /
/ CHp
OH
H
Me H I /
CHZ
H=_ \ OMe
\ / \ /
/ /
CHZ
Table 26 R"~ R"'
OZNHz
H ~ ~ NI
HpN
Formula XXVI
Rtt, Rtt. Rtt, Rtt.
\
H H I / I /
CH=
OH
H
Me H I /
CH2
H2. \ OMe
I\ I/ I\ I/
/ /
CHz
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Table 25a
Rtt° Rtt
OzNH2 I
- / O~
~ H \ I ~N
Formula XXVIa NHZ
Rtt Rtt~ Rtt Rtt
w
H H I I /
/ CHZ
OH
H
Me H I /
CH=
HZ_ Me
\ I
/ I\ /
/ /
CHI
Table 26a
02NHz Rtt~ Rtt
I H
/ N~
\
Formula XXVIIa NHz
Rtt Rtt ~ Rtt Rtt
H H I / I /
H CHz
H
\ _
Me H I /
HZ
H=_ \ OMe
I\ I/ I\ I/
/ / H=
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Table 25b
OZNHZ Rtt' tt'
I
O~
H N
NHz
Formula XXVIb
Rtt, Rtt. Rtt, Rtt.
\
H H I I /
/ CHx
OH
H
Me H ( /
CHZ
Hz_ \ Me
\ / \ /
/ /
CHz
Table 26b
OZNHZ Rtt. Rtt.
H
N~
H N \ I /N
Formula XXVIIb NHZ
Rtt, Rtt. Rtt, Rtt.
w \
H H I I /
/ CHI
OH
H
Me H I /
CHz
Hz. \ OMe
\ / \ /
/ /
CHz
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Table 25c
O2NH2 Rttc Rtt
N~
H N ~ I
Formula XXVIc H2N
Rtt Rttc Rtt Rttc
\
H H I I /
/ CHz
OH
H
Me H I /
CHZ
HZ_ \ OMe
\ I/ I\ I/
/ /
CHZ
Table 26c
O NH Rttc Rtt
2 2
N H
N
~ H N ~
Formula XXVIIc NH2
Rtt Rttc Rtt Rttc
\
H H I / I /
CHz
OH
H
Me H I
CH=
HZ_ \ OMe
I\ I/ I\ I/
/ CHZ
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Table 27
OZNHZ
H
Formula ~~ v m
Rat. R. R, Rm.
\
H H I I /
/ CHz
OH
H
Me H I /
CHx
H z_ Me
\ I/ I\ I/
/ /
CHz
Table 28
OpNH2 R~~ R11
H ~ ~ NH
NON
Formula XXIX
Rat, R~~. Rte, R~~.
H H I I/
/ CHx
OH
H
Me H I /
CHx
Hz_ OMe
\ / I\ /
/ /
CHx
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Table 27a
02NH2 R~~' R~~
I
S
H
NH2
Formula XXVIIIa
R'I'I Rllc R1~ R11 c
H H I I /
/ CHz
OH
H
Me H I /
CHz
Hz_ OMe
I\ I/ I\ /
/ /
CHz
Table 28a
02NHz R~~° R~~
_ _ I H
V N
H I //N
N ~ N
Formula XXIXa
R11 Rllc R11 R1'Ic
\ \
H H I I /
/ CHz
OH
H
Me H I /
CHz
Hz_ \ OMe
\ I/ I\ I/
/ /
CHz
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Table 27b
OpNH2 Rtr Rtr
S~
w w H O y ,
NHZ
Formula XXVIIIb
Rtt, Rtt. Rtt, Rtt.
~ \
H H I I /
/ CHZ
OH
H
Me H I /
CH2
Hz_ \ OMe
\ / I\ /
/ /
CHZ
Table 28b
OpNHp Rtt~ Rtt'
H
N
ii
~N
Formula XXIXb
Rtt. Rtr Rtt. Rtr
H H I I /
/ CH2
OH
H
Me H I /
CHZ
HZ_ \ OMe
\ I/ I\ /
/ /
CHZ
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Table 27c
Rttc Rtt
02NHp
S\
H N
NH 2
Formula XXVIIIc
Rtt Rttc Rtt Rttc
H H I I /
/ CHx
OH
H
Me H I /
CHx
Hx_ \ a
I\ / I\ /
/ /
CHx
Table 28c
OpNHp Rttc Rtt
N ~~ H
/ N\
H N
N
Formula XXIXc
Rtt Rttc Rtt Rttc
\ \
H H I I /
/ CHx
OH
H
Me H I /
CHx
H x. OMe
I\ / I\ /
/ /
CHx
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Table 29
R~~~ R~~
02NHz
1
N
H
N NHz
Formula XXX
R~~~ R~~~ R~~~ R~~
\ \
H H I I /
/ CHy
OH
H
Me H I /
CHZ
Hz_ \ OMe
I\ I/ I\ I/
/ /
CHZ
Table 29a
OpNHp Roc R~r
N N
H N \ I ~NH2
'N
Formula XXXa
Rtt~ Rllc Rtl~ Rltc
H H I I /
/ CHz
OH
H
Me H I /
CHZ
H z. Me
I\ I/ I\ I/
/ /
CH2
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Table 29b
OZNHp Rtr Rtr
H
N
-N H z
'N
Formula XXXb
Rtt, R. Rtt, Rtt.
\ \
H H I I /
/ CHI
OH
H
Me H I /
CHp
Hx_ \ OMe
\ / \ I/
/ /
CHZ
Table 29c
Rttc Rtt
02NHp _
/ N
N ~ ~NH2
N
Formula XXXc
Rtt Ritc Rtt Rttc
H H I I /
/ CHp
OH
H
Me H I /
CHZ
H~_ \ OMe
\ / \ /
/ /
CHz
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Also preferred are compounds according to Tables 1 through Table 24c,
wherein the following groups:
02NH2 02NH2
/ ~ / ~ and ~A/ gyp/
R5 5
when they occur in each of the formulae of the Tables are exchanged for a
group
having the carboxamide group in a reverse horizontal orientation as follows:
02NH2 02NH2
/ ~ / I- and ~ A/ ~ p / I-
R5 R5
wherein the RS substituent is the hydrogen or other amino substituent shown in
the
respective Tables 1 through 24c.
This invention also encompasses all pharmaceutically acceptable isomers,
salts, hydrates and solvates of the compounds of formulas I, II and III. In
addition,
the compounds of formulas I, II and III can exist in various isomeric and
tautomeric
forms, and all such forms are meant to be included in the invention, along
with
pharmaceutically acceptable salts, hydrates and solvates of such isomers and
tautomers.
The compounds of this invention may be isolated as the free acid or base or
converted to salts of various inorganic and organic acids and bases. Such
salts are
within the scope of this invention. Non-toxic and physiologically compatible
salts
are particularly useful although other less desirable salts may have use in
the
processes of isolation and purification.
A number of methods are useful for the preparation of the salts described
above and are known to those skilled in the art. For example, the free acid or
free
base form of a compound of one of the formulas above can be reacted with one
or
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more molar equivalents of the desired acid or base in a solvent or solvent
mixture in
which the salt is insoluble, or in a solvent like water after which the
solvent is
removed by evaporation, distillation or freeze drying. Alternatively, the free
acid or
base form of the product may be passed over an ion exchange resin to form the
S desired salt or one salt form of the product may be converted to another
using the
same general process.
Prodrug Derivatives of Compounds
This invention also encompasses prodrug derivatives of the compounds
contained herein. The term "prodrug" refers to a pharmacologically inactive
derivative of a parent drug molecule that requires biotransformation, either
spontaneous or enzymatic, within the organism to release the active drug.
Prodrugs
are variations or derivatives of the compounds of this invention which have
groups
cleavable under metabolic conditions. Prodrugs become the compounds of the
invention which are pharmaceutically active in vivo, when they undergo
solvolysis
1 S under physiological conditions or undergo enzymatic degradation. Prodrug
compounds of this invention may be called single, double, triple etc.,
depending on
the number of biotransformation steps required to release the active drug
within the
organism, and indicating the number of functionalities present in a precursor-
type
form. Prodrug forms often offer advantages of solubility, tissue
compatibility, or
delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs,
pp.
7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of
Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA,
1992).
Prodrugs commonly known in the art include acid derivatives well known to
practitioners of the art, such as, for example, esters prepared by reaction of
the
parent acids with a suitable alcohol, or amides prepared by reaction of the
parent
acid compound with an amine, or basic groups reacted to form an acylated base
derivative. Moreover, the prodrug derivatives of this invention may be
combined
with other features herein taught to enhance bioavailability.
As mentioned above, the compounds of this invention find utility as
therapeutic agents for disease states in mammals which have disorders of
coagulation such as in the treatment or prevention of unstable angina,
refractory
angina, myocardial infarction, transient ischemic attacks, thrombotic stroke,
embolic
stroke, disseminated intravascular coagulation including the treatment of
septic
shock, deep venous thrombosis in the prevention of pulinonary embolism or the
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treatment of reocclusion or restenosis of reperfused coronary arteries.
Further, these
compounds are useful for the treatment or prophylaxis of those diseases which
involve the production and/or action of factor Xa/prothrombinase complex. This
includes a number of thrombotic and prothrombotic states in which the
coagulation
cascade is activated which include but are not limited to, deep venous
thrombosis,
pulmonary embolism, myocardial infarction, stroke, thromboembolic
complications
of surgery and peripheral arterial occlusion.
Accordingly, a method for preventing or treating a condition in a mammal
characterized by undesired thrombosis comprises administering to the mammal a
therapeutically effective amount of a compound of this invention. In addition
to the
disease states noted above, other diseases treatable or preventable by the
administration of compounds of this invention include, without limitation,
occlusive
coronary thrombus formation resulting from either thrombolytic therapy or
percutaneous transluminal coronary angioplasty, thrombus formation in the
venous
vasculature, disseminated intravascular coagulopathy, a condition wherein
there is
rapid consumption of coagulation factors and systemic coagulation which
results in
the formation of life-threatening thrombi occurring throughout the
microvasculature
leading to widespread organ failure, hemorrhagic stroke, renal dialysis, blood
oxygenation, and cardiac catheterization.
The compounds of the invention also find utility in a method for inhibiting
the coagulation biological samples, which comprises the administration of a
compound of the invention.
The compounds of the present invention may also be used in combination
with other therapeutic or diagnostic agents. In certain preferred embodiments,
the
compounds of this invention may be coadministered along with other compounds
typically prescribed for these conditions according to generally accepted
medical
practice such as anticoagulant agents, thrombolytic agents, or other
antithrombotics,
including platelet aggregation inhibitors, tissue plasminogen activators,
urokinase,
prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of
the
present invention may act in a synergistic fashion to prevent reocclusion
following a
successful thrombolytic therapy and/or reduce the time to reperfusion. These
compounds may also allow for reduced doses of the thrombolytic agents to be
used
and therefore minimize potential hemorrhagic side-effects. The compounds of
this
invention can be utilized in vivo, ordinarily in mammals such as primates,
(e.g.
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humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
The biological properties of the compounds of the present invention can be
readily characterized by methods that are well known in the art, for example
by the
in vitro protease activity assays and in vivo studies to evaluate
antithrombotic
S efficacy, and effects on hemostasis and hematological parameters, such as
are
illustrated in the examples.
Diagnostic applications of the compounds of this invention will typically
utilize formulations in the form of solutions or suspensions. In the
management of
thrombotic disorders the compounds of this invention may be utilized in
compositions such as tablets, capsules or elixirs for oral administration,
suppositories, sterile solutions or suspensions or injectable administration,
and the
like, or incorporated into shaped articles. Subjects in need of treatment
(typically
mammalian) using the compounds of this invention can be administered dosages
that
will provide optimal efficacy. The dose and method of administration will vary
from subject to subject and be dependent upon such factors as the type of
mammal
being treated, its sex, weight, diet, concurrent medication, overall clinical
condition,
the particular compounds employed, the specific use for which these compounds
are
employed, and other factors which those skilled in the medical arts will
recognize.
Formulations of the compounds of this invention are prepared for storage or
administration by mixing the compound having a desired degree of purity with
physiologically acceptable carriers, excipients, stabilizers etc., and may be
provided
in sustained release or timed release formulations. Acceptable carriers or
diluents
for therapeutic use are well known in the pharmaceutical field, and are
described, for
example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R.
Gennaro edit. 1985). Such materials are nontoxic to the recipients at the
dosages
and concentrations employed, and include buffers such as phosphate, citrate,
acetate
and other organic acid salts, antioxidants such as ascorbic acid, low
molecular
weight (less than about ten residues) peptides such as polyarginine, proteins,
such as
serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as
polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic
acid, or
arginine, monosaccharides, disaccharides, and other carbohydrates including
cellulose or its derivatives, glucose, mannose or dextrins, chelating agents
such as
EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium
and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
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Dosage formulations of the compounds of this invention to be used for
therapeutic administration must be sterile. Sterility is readily accomplished
by
filtration through sterile membranes such as 0.2 micron membranes, or by other
conventional methods. Formulations typically will be stored in lyophilized
form or
as an aqueous solution. The pH of the preparations of this invention typically
will
be 3-11, more preferably 5-9 and most preferably 7-8. It will be understood
that use
of certain of the foregoing excipients, carriers, or stabilizers will result
in the
formation of cyclic polypeptide salts. While the preferred route of
administration is
by injection, other methods of administration are also anticipated such as
orally,
intravenously (bolus and/or infusion), subcutaneously, intramuscularly,
colonically,
rectally, nasally, transdermally or intraperitoneally, employing a variety of
dosage
forms such as suppositories, implanted pellets or small cylinders, aerosols,
oral
dosage formulations and topical formulations such as ointments, drops and
dermal
patches. The compounds of this invention are desirably incorporated into
shaped
articles such as implants which may employ inert materials such as
biodegradable
polymers or synthetic silicones, for example, Silastic, silicone rubber or
other
polymers commercially available.
The compounds of the invention may also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles, large
unilamellar
vesicles and multilamellar vesicles. Liposomes can be formed from a variety of
lipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of this invention may also be delivered by the use of
antibodies, antibody fragments, growth factors, hormones, or other targeting
moieties, to which the compound molecules are coupled. The compounds of this
invention may also be coupled with suitable polymers as targetable drug
Garners.
Such polymers can include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-
propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore,
compounds of the 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, polycyanoacrylates and cross linked or amphipathic block
copolymers of hydrogels. Polymers and semipermeable polymer matrices may be
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formed into shaped articles, such as valves, stems, tubing, prostheses and the
like.
Therapeutic compound liquid formulations generally are placed into a
container having a sterile access port, for example, an intravenous solution
bag or
vial having a stopper pierceable by hypodermic injection needle.
Therapeutically effective dosages may be determined by either in vitro or in
vivo methods. For each particular compound of the present invention,
individual
determinations may be made to determine the optimal dosage required. The range
of
therapeutically effective dosages will be influenced by the route of
administration,
the therapeutic objectives and the condition of the patient. For injection by
hypodermic needle, it may be assumed the dosage is delivered into the body's
fluids.
For other routes of administration, the absorption efficiency must be
individually
determined for each compound by methods well known in pharmacology.
Accordingly, it may be necessary for the therapist to titer the dosage and
modify the
route of administration as required to obtain the optimal therapeutic effect.
The
determination of effective dosage levels, that is, the dosage levels necessary
to
achieve the desired result, will be readily determined by one skilled in the
art.
Typically, applications of compound are commenced at lower dosage levels, with
dosage levels being increased until the desired effect is achieved.
The compounds of the invention can be administered orally or parenterally in
an effective amount within the dosage range of about 0.1 to 100 mg/kg,
preferably
about 0.5 to 50 mg/kg and more preferably about 1 to 20 mglkg on a regimen in
a
single or 2 to 4 divided daily doses and/or continuous infusion.
Typically, about 5 to S00 mg of a compound or mixture of compounds of this
invention, as the free acid or base form or as a pharmaceutically acceptable
salt, is
compounded with a physiologically acceptable vehicle, carrier, excipient,
binder,
preservative, stabilizer, dye, flavor etc., as called for by accepted
pharmaceutical
practice. The amount of active ingredient in these compositions is such that a
suitable dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the
like are binders such as acacia, corn starch or gelatin, and excipients such
as
microcrystalline cellulose, disintegrating agents like corn starch or alginic
acid,
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lubricants such as magnesium stearate, sweetening agents such as sucrose or
lactose,
or flavoring agents. When a dosage form is a capsule, in addition to the above
materials it may also contain liquid Garners such as water, saline, or a fatty
oil.
Other materials of various types may be used as coatings or as modifiers of
the
physical form of the dosage unit. Sterile compositions for injection can be
formulated according to conventional pharmaceutical practice. For example,
dissolution or suspension of the active compound in a vehicle such as an oil
or a
synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
Buffers,
preservatives, antioxidants and the like can be incorporated according to
accepted
pharmaceutical practice.
Preparation of Com op unds
The compounds of the present invention may be synthesized by either solid
or liquid phase methods described and referenced in standard textbooks, or by
a
1 S combination of both methods. These methods are well known in the art. See,
Bodanszky, "The Principles of Peptide Synthesis", Hafner, et al., Eds.,
Springer-
Verlag, Berlin, 1984.
Starting materials used in any of these methods are commercially available
from chemical vendors such as Aldrich, Sigma, Nova Biochemicals, Bachem
Biosciences, and the like, or may be readily synthesized by known procedures.
Reactions are carned out in standard laboratory glassware and reaction
vessels under reaction conditions of standard temperature and pressure, except
where
otherwise indicated.
During the synthesis of these compounds, the functional groups of the amino
acid derivatives used in these methods are protected by blocking groups to
prevent
cross reaction during the coupling procedure. Examples of suitable blocking
groups
and their use are described in "The Peptides: Analysis, Synthesis, Biology",
Academic Press, Vol. 3 (Gross, et al., Eds., 1981) and Vol. 9 (1987), the
disclosures
of which are incorporated herein by reference.
Non-limiting exemplary synthesis schemes are outlined directly below, and
specific steps are described in the Examples. The reaction products are
isolated and
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purified by conventional methods, typically by solvent extraction into a
compatible
solvent. The products may be fiuther purified by column chromatography or
other
appropriate methods.
c em 1
H ~ ~ ~ H BuLi, [(CH3)zCHO]3B
W S_CI 2 S_N
O I / O 1 N HCI, THF
TEA DCM
NH2
HO, ,OH Pd(Ph3P)4, Bu4NBr, NaOH, toluene I
B
O ~
I / O H2N ~ ~ Br I ~ S-NH~
~O
a 2
N HtB a
COzH HzN ~ O-S-O
O O
O
N OMe
OMe CN
HCI. HN i
BOP, DIEA, DMF CN AIMe3, DCM
O O SOZNHtBu
_ _ 1. HCI, MeOH
~NH ~ ~ ~ ~ 2. NH40Ac, MeOH
C /~/7N
O O SOZNHz
~NH
HN NHz
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Scheme 3
Br + ~ pdz(dbay~, (s?-BINAP I ~ N~ T~ ~ N
N COOtBu NaOtBu, toluene, 90°C ~ COOtBu ~ , COOH
H
CN CN CN
O
~ r NH2 / \ ~~ . '
SOzNHtBu \ / H ~~~ ~ TFA / \ \ /
'-' ~J
BOP, Et3N, DMF SOZNHtBu ' % SOZNHZ \ ~ N
CN 0 CN
1.NHzOH.HCI, Et3N, ethanol, 40 °C / \
2.Ao20, AcOH
3.50psi H2, 10%Pd/C, methanol SOZNHz
HZN NH
c a e4
~ Br + Pd2(dbay~, (srBINAP ~ N~ T~ ~ N
i ~COOtBu NaOtBu, toluene, 90°C I ~ COOtBu ~ , COO
CN H CN CN
r v ~ r N~
N S~~ / ~ N~,~..
SOGz, methanol ~ 2 \ / H
COOMe AIMS, DCM
SOzN HtBu
CN 1 /
O CN
1.HC1, methanol -
2.NH40Ac, methanol, reflux / ~ N~~,,~.
/ H I~N
SOZNHz F
1 /
HZN ~NH
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Scheme 5
r v ~ , N H2
Br N' J F
Pd2(dbay~, (s~BINAP_ I ~ TI SOZNHtBu
'N"COOEt NaOtBu, toluene, 90°C i COOEt AIMe3, DCM
CN H CN
CN N
NH
O
N 1.H2S, Py, Et3N O
2.Mel, Acetone
- 3.NH40Ac, methanol ~ \ N N
SOZNHtBu F 4.TFA, reflux \ / H
SOZNHZ F
the
r v ~, Nhh
Br
+ Pd2(dba~, (s~BINAP_ I ~ N SOpNHtBu
~COOEt NaOtBu, toluene, 90°C ~ COOEt AIM DCM
CN H CN
CN N
O 'NH
/ \ N I.HzS, Py, Et3N O I r
2.Mel, Acetone
3.NH40Ac, methanol ~ \ N N
SOzNHtBu CI 4.TFA, reflux \ ~ H
SOzNI-t~ CI
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ce
Br
~ Pd2(dbay~, (s}~BINAP w N~ TFA w N
+ ~COOtBu o ~ , COOtBu ~ COOH
NaOtBu, toluene, 90 C I i
CN H CN CN
~r_v ~ i NHz L
N SO NHfBu / \ N~ '~~.
SOG2, methand ~ 2 \ / H
COOMe ~M ,DCM
CN ~ S02NHtBu C11 ~
CN
1.HC1, methanol
2.NH40Ac, methanol, reflux
eme 8
r v ~ , N~
Br Pd2(dbay~, (srBINAP ~ N SazNHtBu
~COOEt NaOtBu, tduene, 90°C ~ COOEt AIM DCM
CN H CN
CN
O
1.NH20H.HG, Et3N, ethanol, 40 °C
/ \ \ / N N 2Acz0, AcOH
H 3.50psi Hz, 10%Pd/C, methand
4.TFA, reflux
S4zN HBu
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Compositions and Formulations
The compounds of this invention may be isolated as the free acid or base or
converted to salts of various inorganic and organic acids and bases. Such
salts are
within the scope of this invention. Non-toxic and physiologically compatible
salts
are particularly useful although other less desirable salts may have use in
the
processes of isolation and purification.
A number of methods are useful for the preparation of the salts described
above and are known to those skilled in the art. For example, reaction of the
free
acid or free base form of a compound of the structures recited above with one
or
more molar equivalents of the desired acid or base in a solvent or solvent
mixture in
which the salt is insoluble, or in a solvent like water after which the
solvent is
removed by evaporation, distillation or freeze drying. Alternatively, the free
acid or
base form of the product may be passed over an ion exchange resin to form the
desired salt or one salt form of the product may be converted to another using
the
same general process.
Diagnostic applications of the compounds of this invention will typically
utilize formulations such as solution or suspension. In the management of
thrombotic disorders the compounds of this invention may be utilized in
compositions such as tablets, capsules or elixirs for oral administration,
suppositories, sterile solutions or suspensions or injectable administration,
and the
like, or incorporated into shaped articles. Subjects in need of treatment
(typically
mammalian) using the compounds of this invention can be administered dosages
that
will provide optimal efficacy. The dose and method of administration will vary
from subject to subject and be dependent upon such factors as the type of
mammal
being treated, its sex, weight, diet, concurrent medication, overall clinical
condition,
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the particular compounds employed, the specific use for which these compounds
are
employed, and other factors which those skilled in the medical arts will
recognize.
Formulations of the compounds of this invention are prepared for storage or
administration by mixing the compound having a desired degree of purity with
physiologically acceptable carriers, excipients, stabilizers etc., and may be
provided
in sustained release or timed release formulations. Acceptable carriers or
diluents
for therapeutic use are well known in the pharmaceutical field, and are
described, for
example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R.
Gennaro edit. 1985). Such materials are nontoxic to the recipients at the
dosages
and concentrations employed, and include buffers such as phosphate, citrate,
acetate
and other organic acid salts, antioxidants such as ascorbic acid, low
molecular
weight (less than about ten residues) peptides such as polyarginine, proteins,
such as
serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as
polyvinalpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic
acid, or
arginine, monosaccharides, disaccharides, and other carbohydrates including
cellulose or its derivatives, glucose, mannose or dextrins, chelating agents
such as
EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium
and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
Dosage formulations of the compounds of this invention to be used for
therapeutic administration must be sterile. Sterility is readily accomplished
by
filtration through sterile membranes such as 0.2 micron membranes, or by other
conventional methods. Formulations typically will be stored in lyophilized
form or
as an aqueous solution. The pH of the preparations of this invention typically
will
be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to
8.
It will be understood that use of certain of the foregoing excipients,
carriers, or
stabilizers will result in the formation of cyclic polypeptide salts. While
the
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preferred route of administration is by injection, other methods of
administration are
also anticipated such as intravenously (bolus and/or infusion),
subcutaneously,
intramuscularly, colonically, rectally, nasally or intraperitoneally,
employing a
variety of dosage forms such as suppositories, implanted pellets or small
cylinders,
aerosols, oral dosage formulations and topical formulations such as ointments,
drops
and dermal patches. The compounds of this invention are desirably incorporated
into shaped articles such as implants which may employ inert materials such as
biodegradable polymers or synthetic silicones, for example, Silastic, silicone
rubber
or other polymers commercially available.
The compounds of this invention may also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles, large
unilamellar
vesicles and multilamellar vesicles. Liposomes can be formed from a variety of
lipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of this invention may also be delivered by the use of
antibodies, antibody fragments, growth factors, hormones, or other targeting
moieties, to which the compound molecules are coupled. The compounds of this
invention may also be coupled with suitable polymers as targetable drug
carriers.
Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-
propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore,
the
factor Xa inhibitors of this 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, polycyanoacrylates and cross linked or amphipathic block
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copolymers of hydrogels. Polymers and semipermeable polymer matrices may be
formed into shaped articles, such as valves, stems, tubing, prostheses and the
like.
Therapeutic compound liquid formulations generally are placed into a
container having a sterile access port, for example, an intravenous solution
bag or
vial having a stopper pierceable by hypodermic injection needle.
Therapeutically effective dosages may be determined by either in vitro or in
vivo methods. For each particular compound of the present invention,
individual
determinations may be made to determine the optimal dosage required. The range
of
therapeutically effective dosages will naturally be influenced by the route of
administration, the therapeutic objectives, and the condition of the patient.
For
injection by hypodermic needle, it may be assumed the dosage is delivered into
the
body's fluids. For other routes of administration, the absorption efficiency
must be
individually determined for each inhibitor by methods well known in
pharmacology.
Accordingly, it may be necessary for the therapist to titer the dosage and
modify the
route of administration as required to obtain the optimal therapeutic effect.
The
determination of effective dosage levels, that is, the dosage levels necessary
to
achieve the desired result, will be within the ambit of one skilled in the
art.
Typically, applications of compound are commenced at lower dosage levels, with
dosage levels being increased until the desired effect is achieved.
A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg,
preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from
about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compounds of this
invention may be administered several times daily, and other dosage regimens
may
also be useful.
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Typically, about 0.5 to 500 mg of a compound or mixture of compounds of
this invention, as the free acid or base form or as a pharmaceutically
acceptable salt,
is compounded with a physiologically acceptable vehicle, Garner, excipient,
binder,
preservative, stabilizer, dye, flavor etc., as called for by accepted
pharmaceutical
S practice. The amount of active ingredient in these compositions is such that
a
suitable dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the
like are a binder such as acacia, corn starch or gelatin, and excipient such
as
microcrystalline cellulose, a disintegrating agent like corn starch or alginic
acid, a
lubricant such as magnesium stearate, a sweetening agent such as sucrose or
lactose,
or a flavoring agent. When a dosage form is a capsule, in addition to the
above
materials it may also contain a liquid carrier such as water, saline, a fatty
oil. Other
materials of various types may be used as coatings or as modifiers of the
physical
form of the dosage unit. Sterile compositions for injection can be formulated
according to conventional pharmaceutical practice. For example, dissolution or
suspension of the active compound in a vehicle such as an oil or a synthetic
fatty
vehicle like ethyl oleate, or into a liposome may be desired. Buffers,
preservatives,
antioxidants and the like can be incorporated according to accepted
pharmaceutical
practice.
In practicing the methods of this invention, the compounds of this invention
may be used alone or in combination, or in combination with other therapeutic
or
diagnostic agents. In certain preferred embodiments, the compounds of this
inventions may be coadministered along with other compounds typically
prescribed
for these conditions according to generally accepted medical practice, such as
anticoagulant agents, thrombolytic agents, or other antithrombotics, including
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platelet aggregation inhibitors, tissue plasminogen activators, urokinase,
prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of
this
invention can be utilized in vivo, ordinarily in mammals such as primates,
such as
humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
The preferred compounds of the present invention are characterized by their
ability to inhibit thrombus formation with acceptable effects on classical
measures of
coagulation parameters, platelets and platelet function, and acceptable levels
of
bleeding complications associated with their use. Conditions characterized by
undesired thrombosis would include those involving the arterial and venous
vasculature.
With respect to the coronary arterial vasculature, abnormal thrombus
formation characterizes the rupture of an established atherosclerotic plaque
which is
the major cause of acute myocardial infarction and unstable angina, as well as
also
characterizing the occlusive coronary thrombus formation resulting from either
thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA).
With respect to the venous vasculature, abnormal thrombus formation
characterizes the condition observed in patients undergoing major surgery in
the
lower extremities or the abdominal area who often suffer from thrombus
formation
in the venous vasculature resulting in reduced blood flow to the affected
extremity
and a predisposition to pulmonary embolism. Abnormal thrombus formation
further
characterizes disseminated intravascular coagulopathy commonly occurs within
both
vascular systems during septic shock, certain viral infections and cancer, a
condition
wherein there is rapid consumption of coagulation factors and systemic
coagulation
which results in the formation of life-threatening thrombi occurring
throughout the
microvasculature leading to widespread organ failure.
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The compounds of this present invention, selected and used as disclosed
herein, are believed to be useful for preventing or treating a condition
characterized
by undesired thrombosis, such as (a) the treatment or prevention of any
thrombotically mediated acute coronary syndrome including myocardial
infarction,
unstable angina, refractory angina, occlusive coronary thrombus occurnng post-
thrombolytic therapy or post-coronary angioplasty, (b) the treatment or
prevention of
any thrombotically mediated cerebrovascular syndrome including embolic stroke,
thrombotic stroke or transient ischemic attacks, (c) the treatment or
prevention of
any thrombotic syndrome occurring in the venous system including deep venous
thrombosis or pulmonary embolus occurring either spontaneously or in the
setting of
malignancy, surgery or trauma, (d) the treatment or prevention of any
coagulopathy
including disseminated intravascular coagulation (including the setting of
septic
shock or other infection, surgery, pregnancy, trauma or malignancy and whether
1 S associated with multi-organ failure or not), thrombotic thrombocytopenic
purpura,
thromboangiitis obliterans, or thrombotic disease associated with heparin
induced
thrombocytopenia, (e) the treatment or prevention of thrombotic complications
associated with extracorporeal circulation (e.g. renal dialysis,
cardiopulmonary
bypass or other oxygenation procedure, plasmapheresis), (f) the treatment or
prevention of thrombotic complications associated with instrumentation (e.g.
cardiac
or other intravascular catheterization, intra-aortic balloon pump, coronary
stmt or
cardiac valve), and (g) those involved with the fitting of prosthetic devices.
Anticoagulant therapy is also useful to prevent coagulation of stored whole
blood and to prevent coagulation in other biological samples for testing or
storage.
Thus the compounds of this invention can be added to or contacted with any
medium
containing or suspected to contain factor Xa and in which it is desired that
blood
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coagulation be inhibited, e.g., when contacting the mammal's blood with
material
such as vascular grafts, stems, orthopedic prostheses, cardiac stents, valves
and
prostheses, extra corporeal circulation systems and the like.
Without further description, it is believed that one of ordinary skill in the
art
can, using the preceding description and the following illustrative examples,
make
and utilize the compounds of the present invention and practice the claimed
methods. The following working examples therefore, specifically point out
preferred embodiments of the present invention, and are not to be construed as
limiting in any way the remainder of the disclosure.
EXAMPLES
Exam
N
,COOtBu
CN
To a solution of 3-bromobenzonitrile (2.73g, l5mmol), H(L)-Proline-OtBu
(5.14g,
30mmo1), sodium tert-butoxide (2.02g, 2lmmol) and (s)-(-)2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl (186mg, 0.3mmo1) in toluene (30m1) was
added tris(dibenzylideneactone)dipalladium (0) (137mg, O.l5mmol). The mixture
was stirred at 90 °C for 6 hrs. After the filtration of the solid, the
filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography using solvent system 10% ethyl acetate in hexane as eluent to
give
the title compound as a light yellowish oil (336mg, 82%). ES-MS (M+H)+ = 273.
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E a
N
1COOH
CN
The compound of example 1 (1.4g, S.l5mmol) was dissolved in trifluoroacetic
acid
(5m1). The mixture was stirred at room temperature for 5 hrs. The solvent was
evaporated in vacuo to give the title compound (1.14g, 100%). ES-MS (M+H)+ _
217.
am 1e 3
/ \
S02NHtBu
To a solution of tert-butylamine (5.73g, 78.4mmo1) and triethylamine (16.6m1,
1 l9mmol) in dichloromethane (200m1) in an ice bath was added benzenesulfonyl
chloride (13.85g, 78.4mmo1) dropwise. The mixture was stirred at room
temperature
overnight. It was washed with saturated sodium carbonate (60m1) and brine
(60m1).
The organic layer was separated, and the aqueous layer was extracted with
dichloromethane (2xSOm1). The combined organic extracts were dried over
magnesium sulfate. The solvent was evaporated in vacuo to give the title
compound
as a light yellowish solid (15.92g, 95%). ES-MS (M+H)+ = 214.
Example 4
/ \ B~oHn
S02NHtBu
To a solution of the compound of example 3 (15.92g, 74.7mmo1) in
tetrahydrofuran
(200m1) in an ice bath was added 1.6M n-butyllithium in hexane (100m1,
164mmo1)
dropwise over 30 minutes. The mixture remained a clear solution. In an ice
bath it
was added triisopropylborate (24.1m1, 104mmo1) dropwise. The mixture was
stirred
at room temperature for 3.Shrs, solution becoming cloudy. After it was cooled
in an
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ice bath, 1N hydrochloride (200m1) was added. The mixture was stirred at room
temperature overnight. It was extracted with ether (2x50m1). The organic
extract was
washed with 1N sodium hydroxide (2x60m1). The aqueous solution was acidified
to
pH=1 with 6N hydrochloride, and then extracted with ether (2x100m1). The ether
extract was dried over magnesium sulfate, and concentrated in vacuo. The crude
product was recrystallized by ether and hexane to give the title compound as a
while
solid (1 1.5g, 60%). ES-MS (M+H)+ = 258.
Example 5
/ \ \ / NHz
S02NHtBu
To a solution of the compound of example 4 (6.4g, 25mmo1) in toluene (120m1)
was
added water (15m1), SN sodium hydroxide (40m1), isopropanol (60m1), 4-
bromoaniline (8.57g, SOmmol) and tetrakis(triphenylphosphine)palladium (0)
(1,44g, 1.25mmo1). The mixture was refluxed for 6 hrs, cooled to room
temperature,
and diluted with ethyl acetate. The organic layer was washed with water
(SOmI), and
dried over magnesium sulfate. After the evaporation of the solvent in vacuo,
the
crude reside was purified by silica gel chromatography using solvent system
30%
ethyl acetate in hexane as eluent to give the title compound as a light
yellowish solid
(5g, 66%). ES-MS (M+H)+ = 305.
e6
0
/ \ N~II~~,
\ / H N
SOzNHtBu 1
CN
To a solution of the compound of example 2 (216mg, lmmol) in dimethylformamide
(5m1) was added triethylamine (279u1, 2mmo1), the compound of example S
(304mg.
lmmol) and the coupling reagent BOP (531mg, l.2mmo1). The mixture was stirred
at room temperature overnight. After the evaporation of the solvent in vacuo,
the
crude~product was purified by silica gel column chromatography using solvent
system 30-50% ethyl acetate in hexane as eluent to give the title compound as
an oil
(220mg, 44%). ES-MS (M+H)+ = 503.
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0
N
S02NH2
CN
The compound of example 6 (220mg, 0,44mmol) was dissolved in trifluoroacetic
acid (3m1). The mixture was refluxed for l.Shrs. The solvent was evaporated in
vacuo to give the title compound as an oil (200mg, 100%). MS-ES (M+H)+ = 447.
Exam 1
0
N~l'"~~
/ H N
S02NH2
H2N -NH
A solution of the compound of example 7 (200mg, 0.44mmol), hydroxylamine
hydrochloride (76mg, l.lmmol) and triethylamine (153u1, l.lmmol) in absolute
1 S ethanol (3m1) was stirred at 40 °C for 15 hrs. After the
evaporation of the solvent in
vacuo, the residue was dissolved in acetic acid (2m1), and acetic anhydride
(83u1,
0,88mmo1) was added. The mixture was stirred at room temperature for 3 hrs. It
was
diluted with absolute methanol (5m1), and 10% Pd/C (catalytic amount) was
added.
The mixture was applied with SOpsi hydrogen for 6 hrs. After the filtration
through
Celite to remove the catalyst, the filtrate was concentrated in vacuo. The
crude
residue was purified by RP-HPLC to give the title compound as a white powder
(89mg, 46%). ES-MS (M+H)+ = 464.
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xam 1e
N
1COOMe
CN
To a solution of the compound of example 2 (210mg, lmmol) in methanol (5m1) in
an ice bath was added thionyl chloride (142u1, 2mmo1) dropwise. The mixture
was
stirred at room temperature overnight. After the concentration in vacuo, it
was
dissolved in dichloromethane (lOml), and washed with water (5m1). The organic
extract was dried over magnesium sulfate, and concentrated in vacuo to give
the title
1 S compound as an oil (290mg, 100%). ES-MS (M+H)+ = 231.
Exam 1ne10
NH2
SOZNHtBu F
To a solution of the compound of example 4 (2.06g, 8mmo1) in toluene (60m1)
was
added water (4m1), 8N sodium hydroxide (8m1), isopropanol (16m1), 2-fluoro-4-
iodoaniline (3.8g, l6mmol) and tetrakis(triphenylphosphine)palladium (0)
(464mg,
0.4mmo1). The mixture was refluxed for 3-4 hrs, cooled to room temperature,
and
diluted with ethyl acetate. The organic layer was washed with water (25m1),
and
dried over magnesium sulfate. After the evaporation of the solvent in vacuo,
the
crude reside was purified by silica gel column chromatography using solvent
system
20-30% ethyl acetate in hexane as eluent to give the title compound as a white
solid
(1.49g, 58%). ES-MS (M+H)+=323.
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Example 11
0
/ \ - N~~r.,
\ / H N
S02NHtBu F 1 ~
CN
To a solution of the compound of example 10 (110mg, 0.34mmol) in
dichloromethane (5m1) was added 2.0M trimethylaluminum in hexane (O.Slml,
1.02mmo1). The mixture was stirred at room temperature for 30 minutes, methane
gas evolved. A solution of the compound of example 9 (78mg, 0.34mmo1) in
dichloromethane (1m1) was added. The mixture was stirred at room temperature
overnight. 1N hydrochloride was added to acidify the solution to pH=2. After
the
addition of water and dichloromethane, the organic layer was separated, and
the
aqueous layer was extracted with dichloromethane. The combined organic
extracts
were dried over magnesium sulfate, and concentrated in vacuo. The crude
residue
was purified by silica gel column chromatography using solvent system 25%
ethyl
acetate in hexane as eluent to give the title compound as a solid (90mg, 51
%). ES-
MS (M+H)+ = 521.
Example 12
0
/ \ - N~~~-.,
\ / H NN
S02NH2 F
HZN -NH
To a solution of the compound of example 11 (90mg, 0.17mmo1) in absolute
methanol (3m1) in an ice bath was saturated with hydrochloride gas for 10
minutes.
The mixture was stirred at room temperature for 3 hrs. After the evaporation
of the
solvent in vacuo, the residue was dissolved in absolute methanol (3m1), and
ammonia acetate (80mg, 1.04mmo1) was added. The mixture was refluxed for 3
hrs.
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The solvent was evaporated in vacuo. The crude residue was purified by RP-HPLC
to give the title compound as a white powder (36mg, 44%). ES-MS (M+H)+ = 482.
Example 13
/ \ \ / NH2
S02NHtBu CI
To a solution of the compound of example 4 (2.06g, 8mmol) in toluene (60m1)
was
added water (4m1), 8N sodium hydroxide (8m1), isopropanol (16m1), 2-chloro-4-
iodoaniline (4.06g, l6mmol) and tetrakis(triphenylphosphine)palladium(0)
(464mg,
0.4mmo1). The mixture was refluxed for 3-4 hrs, cooled to room temperature,
and
diluted with ethyl acetate. The organic layer was washed with water (25m1),
and
dried over magnesium sulfate. After the evaporation of the solvent in vacuo,
the
crude reside was purified by silica gel column chromatography using solvent
system
20-30% ethyl acetate in hexane as eluent to give the title compound as a white
solid
(1.43g, 53%). ES-MS (M+H)+ = 339.
Example 14
0
/ \ - N~~r.,
\ / H N
SOzNHtBu CI1 ~
CN
To a solution of the compound of example 13 (147mg, 0.43mmo1) in
dichloromethane (5m1) was added 2.0M trimethylaluminum in hexane (0.65m1,
1.30mmo1). The mixture was stirred at room temperature for 30 minutes, methane
gas evolved. A solution of the compound of example 9 (100mg, 0.43mmo1) in
dichloromethane (1m1) was added. The mixture was stirred at room temperature
overnight. 1N hydrochloride was added to acidify the solution to pH=2. After
the
addition of water and dichloromethane, the organic layer was separated, and
the
aqueous layer was extracted with dichloromethane. The combined organic
extracts
were dried over magnesium sulfate, and concentrated in vacuo. The crude
residue
was purified by silica gel column chromatography using solvent system 25%
ethyl
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acetate in hexane as eluent to give the title compound as a solid (180mg,
78%). ES-
MS (M+H)+ = 537.
Example 15
To a solution of the compound of example 14 (180mg, 0.34mmo1) in absolute
methanol (3m1) in an ice bath was saturated with hydrochloride gas for 10
minutes.
The mixture was stirred at room temperature for 3 hrs. After the evaporation
of the
solvent in vacuo, the residue was dissolved in absolute methanol (3m1), and
ammonia acetate (155mg, 2mmo1) was added. The mixture was refluxed for 3 hrs.
The solvent was evaporated in vacuo. The crude residue was purified by RP-HPLC
to give the title compound as a white powder (SSmg, 33%). ES-MS (M+H)+ = 498.
Example 16
N
COOEt
CN
To a solution of 3-bromobenzonitrile (1.82g, lOmmol), ethyl pipecolinate
(3.148,
20mmo1), sodium tent-butoxide (1.35g, l4mmol) and (s)-(-)2,2'-bis
(diphenylphosphino)-1,1'-binaphthyl (125mg, 0.2mmo1) in toluene (20m1) was
added tris(dibenzylideneactone)dipalladium (0) (92mg, O.lmmol). The mixture
was
stirred at 90 °C for 6 hrs. After the filtration of the solid, the
filtrate was concentrated
in vacuo. The residue was purified by silica gel column chromatography using
solvent system 5-10% ethyl acetate in hexane as eluent to give the title
compound as
an oil (770mg, 30%). ES-MS (M+H)+ = 259.
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Exam 1p a 17
CN
O
N
H
S02NHtBu
To a solution of the compound of example S (189mg, 0.62mmo1) in
dichloromethane (2m1) was added 2.0M trimethylaluminum in hexane (0.93m1,
1.86mmo1). The mixture was stirred at room temperature for 30 minutes, methane
gas evolved. A solution of the compound of example 16 (160mg, 0.62mmo1) in
dichloromethane (1m1) was added. The mixture was stirred at rood temperature
overnight. 1N hydrochloride was added to acidify the solution to pri=2. After
the
addition of water and dichloromethane, the organic layer was separated, and
the
aqueous layer was extracted with dichloromethane. The combined organic
extracts
were dried over magnesium sulfate, and concentrated in vacuo to give the title
compound as a yellow solid (330mg, 100%). ES-MS (M+H)+ = S 17.
Example 18
NHZ
~NH
O
N
N
H
S02NH2
A solution of the compound of example 17 (330mg, 0.64mmo1), hydroxylamine
hydrochloride (110mg, l.6mmo1) and triethylamine (223u1, l.6mmol) in absolute
ethanol (lOml) was stirred at 40 °C for 15 hrs. After the evaporation
of the solvent in
vacuo, the residue was dissolved in acetic acid (4m1), and acetic anhydride
(121u1,
1.28mmo1) was added. The mixture was stirred at room temperature for 3 hrs. It
was
diluted with absolute methanol (7m1), and 10% Pd/C (catalytic amount) was
added.
The mixture was applied with SOpsi hydrogen for 6 hrs. After the filtration
through
Celite to remove the catalyst, the filtrate was concentrated in vacuo. The
residue was
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dissolved in trifluoroacetic acid (5m1). The mixture was refluxed for l.Shrs.
After
the evaporation of the solvent in vacuo, the crude residue was purified by RP-
HPLC
to give the title compound as a white powder (200mg, 62%). ES-MS (M+H)+ = 478.
Example 19
CN
O
/ ~ - N
H
S02NHtBu F
To a solution of the compound of example 10 (125mg, 0.39mmo1) in
dichloromethane (5m1) was added 2.0M trimethylaluminum in hexane (0.58m1,
1.16mmo1). The mixture was stirred at room temperature for 30 minutes, methane
gas evolved. A solution of the compound of example 16 (100mg, 0.39mmo1) in
dichlodomethane (1m1) was added. The mixture was stirred at room temperature
overnight. 1N hydrochloride was added to acidify the solution to pH=2. After
the
1 S addition of water and dichloromethane, the organic layer was separated and
the
aqueous layer was extracted with dichloromethane. The combined organic
extracts
were dried over magnesium sulfate, and concentrated in vacuo. The crude
residue
was purified by silica gel column chromatography using solvent system 20%
ethyl
acetate in hexane as eluent to give the title compound as a solid (150mg,
72%). ES-
MS (M+H)+ = 535.
Example 20
NH
w ,NH2
O
- N
H
SOZNHz F
To a solution of the compound of example 19 (100mg, 0.19mmol) and
triethylamine
(1m1) in absolute pyridine (lOml) was saturated with hydrosulfide gas for
lOminutes.
The mixture was stirred at room temperature for 1 S hrs. After the evaporation
of the
solvent in vacuo, the green residue was dissolved in acetone (lOml).
Iodomethane
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(118u1, l.9mmo1) was added. The mixture was refluxed for lhr. After the
evaporation of the solvent in vacuo, the residue was dissolved in absolute
methanol
(15m1), and ammonia acetate (176mg, 3.28mmol) was added. The mixture was
refluxed for 3 hrs. After the concentration in vacuo, the residue was
dissolved in
trifluoroacetic acid (5m1), and was refluxed for lhr. The solvent was
evaporated in
vacuo. The crude residue was purified by RP-HPLC to give the title compound as
a
white powder. ES-MS (M+H)+ = 496.
Example 21
CN
O
N
H
SOZNHtBu CI
To a solution of the compound of example 13 (132mg, 0.39mmol) in
dichloromethane (5m1) was added 2.0M trimethylaluminum in hexane (0.58m1,
1.l7mmol). The mixture was stirred at room temperature for 30 minutes, methane
gas evolved. A solution of the compound of example 16 (100mg, 0.39mmo1) in
dichloromethane (1m1) was added. The mixture was stirred at room temperature
overnight. 1N hydrochloride solution was added to acidify the solution to
pH=2.
After the addition of water and dichloromethane, the organic layer was
separated,
and the aqueous layer was extracted with dichloromethane. The combined organic
extracts were dried over magnesium sulfate, and concentrated in vacuo. The
crude
residue was purified by silica gel column chromatography using solvent system
20%
ethyl acetate in hexane as eluent to give the title compound as an oil (160mg,
75%).
ES-MS (M+H)+ = 551.
Ex x In a 22
NH2
NH
O
- N
H
SOZNH2 C~
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To a solution of the compound of example 21 (100mg, 0.18mmo1) and
triethylamine
(1m1) in absolute pyridine (lOml) was saturated with hydrosulfide gas for
lOminutes.
The mixture was stirred at room temperature for 1$ hrs. After the evaporation
of the
solvent in vacuo, the green residue was dissolved in acetone (lOml).
Iodomethane
$ (112u1, l.8mmo1) was added. The mixture was refluxed for lhr. After the
evaporation of the solvent in vacuo, the residue was dissolved in absolute
methanol
(1$m1), and ammonia acetate (166mg, 2.16mmol) was added. The mixture was
refluxed for 3 hrs. After the evaporation of the solvent in vacuo, the residue
was
dissolved in trifluoroacetic acid ($m1), and was refluxed for lhr. The solvent
was
evaporated in vacuo. The crude residue was purified by RP-HPLC to give the
title
compound as a white powder. ES-MS (M+H)+ _ $12.
Exam 1p a 23
H O
N v _OEt
i
CN
1$
To a solution of ethyl bromoacetate (10.6g, 60mmo1), 3-aminobenzonitrile ($g,
40mmo1), and potassium carbonate (17.$g, 120mmo1) in acetonitrile (30m1) was
added potassium iodide (1.4g, 8mmo1). The mixture was heated to reflex for 6
hrs.
The mixture was cooled to room temperature, and solvent was removed in vacuo.
Ether and water were added to the mixture. Organic layer was washed with 1N
hydrochloride and brine, and dried over magnesium sulfate. After the
concentration
in vacuo, the crude residue was purified by silica gel column chromatography
using
solvent system 1$% ethyl acetate in hexane as eluent to give the title
compound as
light yellowish solid (7.94g, 97%). ES-MS (M+H)+ = 20$.
2$
Example 24
I_ o
N v _OEt
CN
To a solution of the compound of example 23 (200mg, lmmol) and cesium
carbonate (6$Omg, 2mmol) in dimethylformamide ($m1) was added iodomethane
(7$u1, 1.2mmol). The mixture was stirred at 90 °C for 2 hrs. After the
filtration of the
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solid, the filtrate was concentrated in vacuo, and the residue was purified by
silica
gel column chromatography using solvent system 15% ethyl acetate in hexane as
eluent to give the title compound as an oil (270mg, 100%). ES-MS (M+H)+ = 219.
Example 25
0
~ ~ / H~N
'-'' ~'
S02NHtBu
CN
To a solution of the compound of example 5 (126mg, 0.41mmo1) in
dichloromethane (5m1) was added 2.0M trimethylaluminum in hexane (0.62m1,
1.24mmo1). The mixture was stirred at room temperature for 30 minutes, methane
gas evolved. A solution of the compound of example 24 (90mg, 0.41mmo1) in
dichlodomethane (1m1) was added. The mixture was stirred at room temperature
overnight. 1N hydrochloride was added to acidify the solution to pH=2. After
the
addition of water and dichloromethane, the organic layer was separated and the
aqueous layer was extracted with dichloromethane. The combined organic
extracts
were dried over magnesium sulfate, and concentrated in vacuo. The crude
residue
was purified by silica gel column chromatography using solvent system 30%
ethyl
acetate in hexane as eluent to give the title compound as a solid (70mg, 36%).
ES-
MS (M+H)+ = 477.
Example 26
0
_ II I
N
H
S02NHtBu
HZN NH
A solution of the compound of example 25 (70mg, 0. l5mmol), hydroxylamine
hydrochloride (26mg, 0.37mmo1) and triethylamine (52u1, 0.37mmo1) in absolute
ethanol (3m1) was stirred at 40 °C for 15 hrs. After the evaporation of
the solvent in
vacuo, the residue was dissolved in acetic acid (3m1), and acetic anhydride
(28u1,
0.3mmol) was added. The mixture was stirred at room temperature for 3 hrs. It
was
diluted with absolute methanol (5m1), and 10% Pd/C (catalytic amount) was
added.
The mixture was applied with 50psi hydrogen for 6 hrs. After the filtration
through
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Celite to remove the catalyst, the filtrate was concentrated in vacuo. The
crude
residue was purified by RP-HPLC to give the title compound as a white powder.
ES-
MS (M+H)+ = 494.
Ex~ lie 27
Bn O
N v 'OEt
CN
To a solution of the compound of example 23 (200mg, lmmol) and cesium
carbonate (650mg, 2mmol) in dimethylformamide (5m1) was added benzyl bromide
(180u1, l.Smmo1). The mixture was stirred at 90 °C for 2 hrs. After the
filtration of
the solid, the filtrate was concentrated in vacuo and the residue was purified
by silica
gel column chromatography using solvent system 10% ethyl acetate in hexane as
eluent to give the title compound as an oil (210mg, 71 %). ES-MS (M+H)+ = 295.
Example 28
O Bn
~ ~ / H~N
S02NHtBu
CN
To a solution of the compound of example 5 (126mg, 0.41mmo1) in
dichloromethane (5m1) was added 2.0M trimethylaluminum in hexane (0.62m1,
1.24mmo1). The mixture was stirred at room temperature for 30 minutes, methane
gas evolved. A solution of the compound of example 27 (120mg, 0.4~1mmo1) in
dichlodomethane (1m1) was added. The mixture was stirred at room temperature
overnight. 1N hydrochloride was added to acidify the solution to pH=2. After
the
addition of water and dichloromethane, the organic layer was separated, and
the
aqueous layer was extracted with dichloromethane. The combined organic
extracts
were dried over magnesium sulfate, and concentrated in vacuo. The crude
residue
was purified by silica gel column chromatography using solvent system 20%
ethyl
acetate in hexane as eluent to give the title compound as a solid (172mg,
76%). ES-
MS (M+H)+ = 553.
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Example 29
OI Bn
N
H
S02NH2
HZN NH
To a solution of the compound of example 28 (100mg, 0.18mmo1) and absolute
S methanol (73u1, l.8mmo1) in ethyl acetate (3m1) in an ice bath was saturated
with
hydrochloride gas for 10 minutes. The mixture was stirred at room temperature
for 3
hrs. After the evaporation of the solvent in vacuo, the residue was dissolved
in
absolute methanol (3m1), and ammonia acetate (83mg, 1.08mmo1) was added. The
mixture was refluxed for 3 hrs. The solvent was evaporated in vacuo. The crude
residue was purified by RP-HPLC to give the title compound as white powder. ES-
MS (M+H)+ = 514.
Example 30
O O
N '~~H~OMe
CN
H-Pro-OMe (3.38 g, 20.4 mmol) and 3-cyano-benzoic acid (3 g, 20.4 mmol) were
dissolved in DMF (100 mL). DIEA (7.28 mL, 40.8 mmol) was added followed by
the addition of the coupling reagent BOP (9.03 g, 20.4 mmol). The solution was
stirred at room temperature for 12 hours. The reaction mixture was diluted in
a
mixture of EtOAc1H20 (100 mL:40 mL). The organic layer was washed with water,
sat. NaHC03, water, brine, dried over MgS04, filtered and solvent evaporated.
The
residue was purified by silica gel column chromatography using solvent system
20%
hexane in EtOAc as eluant to give the title compound. ES-MS (M+H)+ = 259Ø
Example 31
S02NHtBu
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To a solution of tent-Butylamine (41.4g, 566 mmol) and triethylamine (118 mL,
849
mmol) in DCM (1000 mL) in an ice bath, was added benzenesulfonyl chloride (100
g, 566 mmol) dropwise. The mixture was stirred at room temperature overnight.
Water was added to the mixture and organic layer was washed with water, brine,
dried over NazS04, filtered and filtrated evaporated in vacuo to give the
title
compound as light yellowish solid (117.63 g, 97.6%). (M+H)+ = 214.1.
Example 32
B(OH)2
~ S02NHtBu
To a solution of compound of example 31 (53.25 g, 250 mmol) in THF (600 mL) in
an ice bath, was added n-butyllithium in hexane (200 mL, 500 mmol) dropwise. A
thick precipitate was formed when the reaction mixture was warmed up to
10°C.
Triisopropylborate was added keeping the temperature below 35°C. After
1 hr., the
mixture was cooled in an ice bath, 1N HCl (405 mL) was added, and the mixture
was stirred overnight. The mixture was extracted with ether (100 mL) three
times.
The combined organic extracts were extracted with 1N NaOH (130 mL) three
times.
The aqueous extracts were acidified to pH 1 with 12 N HCI, and then extracted
with
ether three times (140 ML). The combined ether extracts were dried over MgS04,
and solvents evaporated in vacuo. Hexane and ether were added and a white
precipitate formed. The solid was collected and washed with 10% ether/hexane
to
give the title compound. (M+H)+ = 257.1.
Exam 1p a 33
S02NHtBu
H2N ~
To a solution of compound of example 32 (6.4 g, 25 mmol) in toluene (120 mL)
was
added water (15 mL), SN NaOH solution (38.5 mL), isopropanol (60 mL), 4-
bromoaniline and tetrakis(triphenylphosphine) palladium(0). The mixture was
refluxed for six hours, cooled to room temperature, diluted with EtOAc. The
organic layer was washed with water, dried with MgS04, filtered and
concentrated.
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This was purified by silica gel column chromatography using solvent system 30%
EtOAc in hexane as eluant to give the title compound (5g, 66%). ES-MS (M+H)+ _
305.1.
Example 34
O O S02NHtBu
I - -
N ''~~~NH
i
CN
To a solution of compound of example 33 (278 mg, 0.92 mmol) in DCM (5 mL) was
added trimethylaluminum (1.37 mL, 2 M in hexane) dropwise. The reaction
mixture
was stirred at room temperature for 30 min. Compound of example 17 (236 mg,
0.92 mmol) in DCM (3 mL) was added dropwise. The mixture was stirred at room
temperature overnight. 2N HCl was added to PH 2 to neutralize excess AlMe3.
Water and DCM were added. The organic layer was dried over MgS04 and
concentrated in vacuo. The obtained resudue was purified by silica gel column
chromatography using solvent system 50% EtOAc in hexane as eluant to give the
title compound. ES-MS (M+Na)+ =553.2.
E~ 1ne35
O O S02NH2
- -
N ,''~NH
HN NH2
A solution of the compound of example 34(96 mg, 0.18 mmol) in MeOH (3 mL)
was treated with a stream of HCl gas for 10 min. at 0°C. The resulting
solution was
capped, stirred at room temperature overnight and evaporated in vacuo. The
residue
was reconstituted in MeOH (3 mL) and the mixture was treated with NH40Ac (69
mg, 0.9 mmol). The reaction mixture was refluxed for 1.5 hrs. and concentrated
in
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vacuo. The obtained residue was purified by RP-HPLC to give the title compound
as a white powder. ES-MS (M+H)+ = 492.0
BIOLOGICAL ACTNITY EXAMPLES
Evaluation of the compounds of this invention is guided by in vitro protease
activity assays (see below) and in vivo studies to evaluate antithrombotic
efficacy,
and effects on hemostasis and hematological parameters.
The compounds of the present invention are dissolved in buffer to give
solutions containing concentrations such that assay concentrations range from
0 to
100 pM. In the assays for thrombin, prothrombinase and factor Xa, a synthetic
chromogenic substrate is added to a solution containing test compound and the
enzyme of interest and the residual catalytic activity of that enzyme is
determined
spectrophotometrically. The IC50 of a compound is determined from the
substrate
turnover. The IC50 is the concentration of test compound giving 50% inhibition
of
the substrate turnover. The compounds of the present invention desirably have
an
ICSp of less than 500 nM in the factor Xa assay, preferably less than 200 nM,
and
more preferred compounds have an IC50 of about 100 nM or less in the factor Xa
assay. The compounds of the present invention desirably have an IC50 of less
than
4.0 pM in the prothrombinase assay, preferably less than 200 nM, and more
preferred compounds have an IC50 of about 10 nM or less in the prothrombinase
assay. The compounds of the present Invention desirably have an ICSO of
greater
than 1.0 pM in the thrombin assay, preferably greater than 10.0 ~,M, and more
preferred compounds have an IC50 of greater than 100.0 ~M in the thrombin
assay.
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Amidol, is Assays for determining_protease inhibition activity
The factor Xa and thrombin assays are performed at room temperature, in
0.02 M Tris~HCl buffer, pH 7.5, containing 0.15 M NaCI. The rates of
hydrolysis of
the para-nitroanilide substrate S-2765 (Chromogenix) for factor Xa, and the
substrate Chromozym TH (Boehringer Mannheim) for thrombin following
preincubation of the enzyme with inhibitor for 5 minutes at room temperature,
and
were determined using the Softmax 96-well plate reader (Molecular Devices),
monitored at 405 nm to measure the time dependent appearance of p-
nitroaniline.
The prothrombinase inhibition assay is performed in a plasma free system
with modifications to the method described by Sinha, U. et al., Thromb. Res.,
Z,
427-436 (1994). Specifically, the activity of the prothrombinase complex is
determined by measuring the time course of thrombin generation using the p-
nitroanilide substrate Chromozym TH. The assay consists of preincubation ( 5
minutes) of selected compounds to be tested as inhibitors with the complex
formed
from factor Xa (0.5 nM), factor Va (2 nM), phosphatidyl serine:phosphatidyl
choline
(25:75, 20 ~,M) in 20 mM Tris~HCl buffer, pH 7.5, containing 0.15 M NaCI, 5 mM
CaCl2 and 0.1% bovine serum albumin. Aliquots from the complex-inhibitor
mixture are added to prothrombin (1 nM) and Chromozym TH (0.1 mM). The rate
of substrate cleavage is monitored at 405 nm for two minutes. Eight different
concentrations of inhibitor are assayed in duplicate. A standard curve of
thrombin
generation by an equivalent amount of untreated complex are used for
determination
of percent inhibition.
Antithrombotic Efficacy in a Rabbit Model of Venous Thrombosis
A rabbit deep vein thrombosis model as described by Hollenbach, S. et al.,
Thromb. Haemost. 71, 357-362 (1994), is used to determine the in-vivo
antithrombotic
activity of the test compounds. Rabbits are anesthetized with LM. injections
of Ketamine,
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Xylazine, and Acepromazine cocktail. A standardized protocol consists of
insertion of a
thrombogenic cotton thread and copper wire apparatus into the abdominal vena
cava of
the anesthetized rabbit. A non-occlusive thrombus is allowed to develop in the
central
venous circulation and inhibition of thrombus growth is used as a measure of
the
S antithrombotic activity of the studied compounds. Test agents or control
saline are
administered through a marginal ear vein catheter. A femoral vein catheter is
used for
blood sampling prior to and during steady state infusion of test compound.
Initiation of
thrombus formation begins immediately after advancement of the cotton thread
apparatus
into the central venous circulation. Test compounds are administered from time
= 30 min
to time = 150 min at which the experiment is terminated. The rabbits are
euthanized and
the thrombus excised by surgical dissection and characterized by weight and
histology.
Blood samples are analyzed for changes in hematological and coagulation
parameters.
Effects of Compounds in Rabbit Venous Thrombosis model
Administration of compounds in the rabbit venous thrombosis model demonstrates
antithrombotic efficacy at the higher doses evaluated. There are no
significant effects of
the compound on the aPTT and PT prolongation with the highest dose (100 pg/kg
+ 2.57
pg/kg/min). Compounds have no significant effects on hematological parameters
as
compared to saline controls. All measurements are an average of all samples
after steady
state administration of vehicle or (D)-Arg-Gly-Arg-thiazole. Values are
expressed as
mean + SD.
Without further description, it is believed that one of ordinary skill in the
art can,
using the preceding description and the following illustrative examples, make
and utilize
the compounds of the present invention and practice the claimed methods.
