Note: Descriptions are shown in the official language in which they were submitted.
WO 01/42198 CA 02410596 2002-06-11 pCT/US00/42819
METHODS FOR PRODUCING 3-CYANO- AND 4-CYANO-BENZOIC ACID DERIUATIUE COMPOUNDS
Field of the Invention
This invention relates to novel processes for producing cyanobenzoic acid
derivative compounds, salts thereof
and intermediates therefor. The invention further relates to improved
catalytic processes for making carboxylic acid
derivatives from substituents on an unsaturated aryl compound.
Background of the Invention
Known processes exist for making cyanobenzoic acid compounds, particularly 4-
cyanobenzoic acid (CAS 619
65-8) and 2-fluoro-4-cyanobenzoic acid (benzoic acid 119, for example, in
reaction Scheme 17 of U.S. Patent
5,731,324, at pages 77-80) compounds from the corresponding 4-aminotoluene and
4-amino-2-fluorotoluene
compounds. However, the starting materials for such process are often very
expensive, have limited availability, and
may be difficult to modify in a good yield. For example, 2-fluoro-4-
cyanobenzoic acid can be prepared from 4-amino-2-
fluoro-toluene using standard methods in the presence of EDCI and DMAP, or the
like. Often the yield for making
derivatives, or the recovery of intermediates are difficult with respect to
nitrites. Oxidation procedures to convert the
methyl group of the toluene to a carboxylic acid group when the nitrite group
is present on the aromatic ring often tend
to have a relatively low yield and sometimes a complicated recovery and
purification. When the presence of both a
carboxylic acid group and the halogen group are desired on the ring, the
procedures become even more difficult and the
low yields are very common, which are not well tolerated. The yield is also
complicated by the fact that the starting
materials are also expensive. Therefore, there is a need for efficient
processes to produce p- and m-cyanobenzoic acid
derivatives land the like with pyridyl derivatives) which are particularly
substituted ortho to the carboxylic acid group
with selected substituents, such as halogens, alcohols or ethers, which use
economically priced starting materials and
higher yielding overall steps than current processes, wherein the processes
can be scaled to industrial levels with
readily available materials and reagents. Such compounds, their intermediates
and salts are useful as functional
groups in a wide variety of industrial and pharmaceutical fields.
Summary of the Invention
The present invention relates to novel processes for producing para or meta
cyanobenzoic acid derivative
compounds wherein up to four of the free hydrogens on the benzene ring may be
replaced with a group such as I, F, Br,
CI, OH, 0-alkyl and the like. Further, the process according to the invention
provides processes for making the
corresponding carboxyl substituted pyridyl compounds having a cyano group
located ortho or meta with respect to the
carboxyl group. Such functional group substituted phenyl and pyridyl compounds
are intermediates for producing
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WO 01/42198 CA 02410596 2002-06-11 pCT/US00/42819
therapeutic agents, for example, far disease states in mammals that have
disorders caused by or impacted by platelet
dependent narrowing of the blood supply.
In accordance with one aspect of the present invention, there is provided a
process far preparing derivatives
of 4-cyanobenzoic acid. The process comprises contacting Z-amino-4-
nitrotoluene with HRINaN03 followed by heating
to form 2-R-substituted 4-nitrotoluene:
CH3
02 ~ R
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by exposing the above
compound to reducing conditions to
reduce the vitro group on the ring to form a 2-R-substituted 4-aminotoluene,
contacting the reduced compound with
NaNO21HC1 followed by the addition of a source of cyanate ion to form 2-R-
substituted 4-cyanotoluene, and oxidizing
the methyl group of the cyano compound to form 2-R-substituted-4-cyanobenzoic
acid.
In accordance with a further aspect of the present invention, there is
provided an alternate method for
preparing derivatives of 4-cyanobenzoic acid. The process comprises contacting
2-amino-4-nitrotoluene with
HRINaN03 followed by heating to form 2-R-substituted 4-nitrotoluene:
CHg
O2 /~ R
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by exposing the above
compound to oxidizing conditions to
oxidize the methyl group an the ring to form 2-R-substituted 4-nitrobenzoic
acid, hydrogenating the vitro group on the
ring to form 2-R-substituted 4-aminobenzoic acid, and contacting the 2-R-
substituted 4-aminobenzoic acid with
NaN021HC1 followed by the addition of a source of cyanate ion to form a 2-R-
substituted 4-cyanobenzoic acid
derivative compound.
In accordance with another aspect of the present invention, there is provided
a process for preparing
derivatives of 3-cyanobenzoic acid. The process comprises contacting 2-amino-5-
nitrotoluene with HRINaN03 followed
by heating to form 5-R-substituted 3-nitrotoluene:
R
/~
02 \ CH 3.
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by hydrogenating the
vitro group on the above compound to
form 5-R-substituted 3-aminotoluene, contacting the 5-R-substituted 3-
aminotoluene with NaNOZIHCI followed by the
addition of a source of cyanate ion to form 5-R-substituted 3-cyanotoluene,
and oxidizing the methyl group on the ring
to form 5-R-substituted 3-cyanobenzoic acid.
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In accordance with a further aspect of the present invention, there is
provided an alternate process for
preparing derivatives of 3-cyanobenzoic acid. The process comprises contacting
2-amino-5-nitrotoluene with
HRINaN03 followed by heating to form 5-R-substituted 3-nitrotoluene:
R
O ~~
\- CH3,
wherein R is hydrogen, alkyl, halo, or alkoxy, followed by oxidizing the
methyl group on the ring to form 5-R-
substituted 3-nitrobenzoic acid, hydrogenating the vitro group on the ring to
form 5-R-substituted 3-aminobenzoic acid,
and contacting the 5-R-substituted 3-aminobenzoic acid with NaNOZIHCI followed
by the addition of a source of
cyanate ion to form 5-R-substituted 3-cyanobenzoic acid.
In accordance with yet another aspect of the present invention, there is
provided a process for preparing 3-
fluoro-4-cyanobenzoic acid. The process comprises contacting 2-chloro-4-
nitrobenzoic acid with a metal fluoride to
cause a halogen exchange to form 2-fluoro-4-nitrobenzoic acid; exposing the 2-
fluoro-4-nitrobenzoic acid to reducing
conditions to reduce the vitro group on the ring to form 2-fluoro-4-
aminobenzoic acid; and contacting the 2-fluoro-4-
aminobenzoic acid fwith NaNOZIHCI followed by the addition of a source of
cyanate ion to form 3-fluoro-4-
cyanobenzoic acid.
Detailed Description of the Invention
Preferred Embodiments
The processes of the present invention are directed to producing p- or m-
cyanobenzoic acid derivative
compounds wherein the up to four of the free hydrogens on the benzene ring may
be replaced with a group such as I, F,
Br, CI, OH, 0-alkyl and the like. The processes further provide for making the
corresponding carboxyl substituted
pyridyl compounds having a cyano group located ortho or meta with respect to
the carboxyl group. Such functional
group substituted phenyl and pyridyl compounds may be used as intermediates
for producing therapeutic agents, for
example, for disease states in mammals that have disorders caused by or
impacted by platelet dependent narrowing of
the blood supply.
In one aspect, the present invention provides a process to convert at least
one amino group present on a
benzene ring or phenyl ring to a hydrogen, halogen group, a hydroxyl group or
an alkoxy group prior to the presence of a
nitrite group on the ring. Preferably, a carboxyl group is present on the ring
or a methyl group on the ring (tolyl or
methyl pyridyl derivative) is oxidized to form a ring carboxyl group prior to
the presence of a nitrite group on the ring as
in Scheme II, but the oxidation may be done after the formation of the nitrite
as in Scheme I. The oxidizing agent is
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preferably KMn04, a ruthenium derivative catalyst, an iridium derivative
catalyst, or the like, wherein sodium
hypochlorite (bleach) or the like is opti,:mally present.
In another preferred aspect, the present invention provides a process for
converting one or more amino
groups on a phenyl or pyridyl ring into a diazonium compound, optionally in
the presence of a tertiary amine or
ammonia, and using a Sandmeyer procedure or the like to replace the diazonium
compound with a desired ring
substitutent group prior to forming a nitrite (cyano group on the ringl. For
example, allowing the diazonium compound
to warm up to room temperature or heating it will ordinarily result in its
replacement with the halogen group utilized to
form the diazonium compound. Preferably at least one vitro group is present as
a substitutent on the ring during such
replacementls) of the amino groupls) via a diazonium derivative compound. In
preferred embodiments, a methyl group
or the like on the ring is oxidized to an aldehyde or carboxyl group prior to
farming a nitrite (cyano group on the ring) as
in Scheme IV, but the oxidation may be done after the formation of the nitrite
as in Scheme III. Once formed, the
carboxyl group on the ring can readily be converted to an ester, carboxamide
derivative or the like, if such derivative is
desired.
After one or both of the above two steps, a vitro group on the phenyl or
pyridyl ring is hydrogenated, such as
by FeIHCI or SnC121HC1, or by catalytic hydrogenation by use of catalysts such
as palladiumlcarbon or nickel, and other
such reductive methods. Essentially, most reducing catalysts will work under
reasonably mild conditions to convert
the vitro group to an amino group. The amino group is then converted to a
diazonium compound, optionally in the
presence of a tertiary amine or ammonia, and a nitrite is formed. Using a
Sandmeyer procedure, or the like, the
diazonium compound is replaced with a cyano group.
In another preferred aspect, a benzoic acid derivative containing a vitro
group and a halogen group such as a
chlorine group is first subjected to a halogen exchange reaction with a metal
salt of a fluoride, such as potassium
fluoride (KFI, to obtain an benzoic acid derivative with a ring fluoro group
in a desired position. The ring vitro group is
then hydrogenated, e.g. by use of FeIHCI or SnCIzIHCI, or by catalytic
hydrogenation by use of catalysts such as
palladiumlcarbon or nickel, and other such reductive methods as described
above, to convert it to an amino group. The
amino group is then converted to a diazonium compound, optionally in the
presence of a tertiary amine or ammonia, and
a nitrite is formed. Using a Sandmeyer procedure, or the like, the diazonium
compound is replaced with a cyano group.
The non-limiting reaction schemes below illustrate the processes according to
preferred embodiments of the
invention with respect to phenyl compounds, but also readily apply to pyridyl
compounds, as well as other heterocylic
compounds. The R substitutent in preferred embodiments set forth below which
occurs on the phenyl ring is a halogen
group which is utilized in the Sandmeyer procedure or a modified Sandmeyer
procedure. Where the diazonium group is
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WO 01/42198 CA 02410596 2002-06-11 pCT~S00/42819
to be replaced with a hydroxyl group, this is accomplished by adding water to
the reaction mixture prior to permitting
the reaction mixture to warm to room temperature. Preferably, the reaction
mixture is at about 0°C. when the water is
added.
Scheme I is directed to the formation of para-cyano benzoic acid derivatives
wherein the carboxyl group is
formed after the cyano group is present on the phenyl ring and is as follows:
SCHEMEI
HR/NaNO 3 w/
tertiary amine
CH3 orNH4Salts \ CH3 Heat \ CH3
S
02ND: "~NH2 S1 02 / NrR O / R
2
2-amino-4-nitrotoluene Reduce
e.g., Aldrich A-5832 S3
Fe & HCl
\ CH3 NaN02 \ CH3
w/ HCl
CI-N2 / R S4 H2 / R
CuCN
\ CH3 SS
C / R Na-Hypochlorite and Tetrabutyl
III ammonium bromide
N S6
3-R-4-methyl-
benzonitrile \ H
C / R
III
N
4-cyano-2-R-
benzoic acid
wherein R is a member selected from hydrogen, halogen, OH, OR' (wherein R' is
alkyl or other lipophilic group). An acid
addition salt, basic salt or the like may be formed of the carboxyl group, if
desired. The formation of esters, acyl
halides and carboxamides from the carboxyl group are contemplated. Such
reactions may be accomplished by
techniques known to those of skill in the art.
Scheme II is directed to the formation of p-cyanobenzoic acid derivatives
wherein the carboxyl group is
formed before a cyano group is present on the phenyl ring (i.e., carboxyl
derivative is not also a nitrilel, the process is
generally as follows:
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SCHEME II
HR/NaNO 3 w/
tertiary amine
w~, , CH 3 or NH 4 Salts ~ \ CH 3 Heat \ CH 3
O N~NH St / S
2 2 02 ~ NCR 02 / R
2-ami no-4-ni trotol uene
e.g., Aldrich A-5832 Oxidize, e.g S3
KMN04
OH Reduce \ OH
Fe & HCl
H~ / R S4 02N / R
SS
NaN02
w/ HCl
\ H
CI-N / R
CuCN
S6
\ H
C / R
III
N
4-cyano-2-R-benzoi c aci d
wherein R is a member selected from hydrogen, halogen, OH, OR' (wherein R' is
alkyl or other lipophilic group). An acid
addition salt, basic salt or the like may be formed of the carboxyl group, if
desired. The formation of esters, acyl
halides and carboxamides from the carboxyl group are contemplated. Such
reactions may be accomplished by
techniques known to those of skill in the art.
Scheme III is directed to the formation of m-cyanobenzoic acid derivatives
wherein the carboxyl group is
formed after the cyano group is present on the phenyl ring and is as follows:
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SCHEME III
HR/NaNO 3 w/
NH tertiary amine
or NH4 Salts _ ~ \ NrR Heat \ R
S
02N~~ CHg SI O ~ CH3 O ~ CHg
2-amino-5-nitrotoluene
e.8., Fluka 08990, Reduce S3
CAS 99-52-5 Fe & HCl
\ R NaNO 2 \ R
w/ HCl
CI-N2 ~ CHg S4 H ~ CH3
CuCN
\ R SS
C ~ / CH Na-Hypochlorite and Tetrabutyl
III 3 ammonium bromide
N S6
3-methyl-4-R- \ R
benzonitrile
C ~ OH
III
N
3-cyano-5-R-
benzoic acid
wherein R is a member selected from hydrogen, halogen, OH, OR' (wherein R' is
alkyl or other lipophilic groupl. An acid
addition salt, basic salt or the like may be formed of the carboxyl group, if
desired. The formation of esters, acyl
halides and carboxamides from the carboxyl group are contemplated. Such
reactions may be accomplished by
techniques known to those of skill in the art.
Scheme IV is directed to the formation of m-cyanobenzoic acid derivatives
wherein the carboxyl group is
formed before a cyano group is present on the phenyl ring (i.e., carboxyl
derivative is not also a nitrilel, the process is
generally as follows:
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SCHEME IV
H R/NaNO 3 w/
tertiary amine
\ NH2 or N114 Salts _ ~ '~ ' N2-R Heat \ R
S
02N / CH3 Sl 02 ' CH3 02 ~ CH3
2-amino-5-nitrotoluene Oxidize, e.g S3
e.g., Fluka 08990,
CAS 99-52-5
\ R Reduce \ R
~ Fe & HC1
H2N / H S4 02N / H
SS O O
\ R NaN02
w/ HCI
Cl-N 2 / H
O
CuCN
S6 \ R
C / H
III O
N
3-cyano-S-R-benzoic acid
wherein R is a member selected from hydrogen, halogen, OH, OR' (wherein R' is
alkyl or other lipophilic groupl. An acid
addition salt, basic salt or the like may be formed of the carboxyl group, if
desired. The formation of esters, acyl
halides and carboxamides from the carboxyl group are contemplated. Such
reactions may be accomplished by
techniques known to those of skill in the art.
Scheme V is directed to the formation of p-cyanobenzoic acid derivatives
wherein the carboxyl group is
already present and a halogen exchange reaction is conducted prior to forming
a nitrite, the process is generally as
follows:
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SCHEME V
O
OH KF OH
O N'~rC~ S1 Reduce
/ F Fe & HCl O
2-chloro-4-nitrobenzoic S2 OH
acid, e.g., Aldrich C59602
H 2N / F
NaN02
O O w/ HCl
OH OH
\ ~ ~ \ S3
C / F S4 CI-N2 / F
4-cyano-2-fluoro
benzoic acid
wherein R is a member selected from hydrogen, halogen, OH, OR' (wherein R' is
alkyl or other lipophilic group). An acid
addition salt, basic salt or the like may be formed of the carboxyl group, if
desired. The formation of esters, acyl
halides and carboxamides from the carboxyl group are contemplated. Such
reactions may be accomplished by
techniques known to those of skill in the art.
As mentioned above, the compounds of this invention find utility as
intermediates for producing therapeutic
agents or as therapeutic agents for the prevention or treatment of thrombosis,
including conditions that are due to
platelet-mediated narrowing of the blood supply, such as those which result
from injury, surgical intervention or
disease. Examples of such indications include, but are not limited to
atherosclerosis and arteriosclerosis, acute
myocardial infarction, chronic stable angina, unstable angina, transient
ischemic attacks and strokes, cerebrovascular
conditions, restenosis, peripheral vascular disease, arterial thrombosis,
preclampsia, embolism, carotid endarterectomy,
anastomosis of vascular grafts, and etc.
Platelet adhesion and aggregation is believed to be an important part of
thrombus formation. This activity is
mediated by a number of platelet adhesive glycoproteins. The binding sites for
fibrinogen, fibronectin and other
clotting factors have been located on the platelet membrane glycoprotein
complex Ilblllla. When a platelet is activated
by an agonist such as thrombin the GPllb-Illa binding site becomes available
to fibrinogen, eventually resulting in
platelet aggregation and clot formation. Thus, intermediate compounds for
producing compounds that effective in the
inhibition of platelet aggregation and reduction of the incidence of clot
formation are useful intermediate compounds.
The compounds produced according to the present invention may also be used as
intermediates in the
formation of compounds that may be administered in combination or concert with
other therapeutic or diagnostic
agents. In certain preferred embodiments, the compounds produced by the
intermediates according to the present
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invention may be co-administered 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 produced from the intermediates
according to the present invention may
act in a synergistic fashion to prevent reocclusion following a successful
thrombolytic therapy andlor reduce the time
to reperfusion. Such compounds may also allow for reduced doses of the
thrombolytic agents to be used and therefore
minimize potential hemorrhagic side-effects. Such compounds can be utilized in
vivo, ordinarily in mammals such as
primates, (e.g. humansl, sheep, horses, cattle, pigs, dogs, cats, rats and
mice, or in vitro.
The nitrite compounds according to the present invention can be converted into
amidino compounds as
described at page 54, lines 16-23, of U.S. Patent 5,731,324, for example.
Namely, the nitrite compounds according to
the invention may be (1 ) reacted with NZS, (2) the resulting intermediate
thioamide can be alkylated with methyl iodine,
(3) the intermediate thioimidate can then be reacted with ammonium acetate to
produce the amidino group. The
amidino group may be optionally protected with a Boc protecting group, before
or after reaction of the carboxyl group
with another compound to produce a derivatized carboxyl group. The Boc
protecting group is optionally removed from
the amidino group by reacting the compound with neat TFA, before or after
reaction of the carboxyl group with the
other compound.
The starting materials used in above processes 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, for example, by using procedures such as indicated above.
Reactions are carried out in standard laboratory glassware and reaction
vessels under reaction conditions of
standard temperature and pressure, except where otherwise indicated, or is
well-known in literature available in the
art. Further, the above procedures of the claimed invention processes my be
carried out on a commercial scale by
utilizing reactors and standard scale-up equipment available in the art for
producing large amounts of compounds in the
commercial environment. Such equipment and scale-up procedures are well-known
to the ordinary practitioner in the
field of commercial chemical production.
During the synthesis of these compounds, amino or acid functional groups may
be protected by blocking
groups to prevent undesired reactions with the amino group during certain
procedures. Examples of suitable blocking
groups are well know in the art. Further, removal of amino blocking groups by
procedures such as acidification or
hydrogenation are well-known in the art.
WO 01/42198 CA 02410596 2002-06-11 pCT~S00/42819
Five non-limiting exemplary synthesis schemes (1-V) shown above, which are
each a preferred embodiment of
the invention comprise the process steps outlined directly above. Further
contemplated are processing steps which
modify the cyano group to a desired functional group or couples the cyano
compound to such groups as commonly
described in the anti-coagulation field, as well as processing steps to modify
or add substituents to the ring. In this
respect, U.S. Patent Application 5,731,324 is incorporated herein in its
entirety by reference. Phenyl groups are
shown, but such processes can be readily adapted for bicyclic ring structures
as well as heterocyclic ring structures
that are common in the anti-coagulation field. Such structures are described
in detail in U.S. Patents 5,731,324 and
5,618,843, for example and are incorporated herein by reference. The reaction
products are isolated and purified by
conventional methods, typically by solvent extraction into a compatible
solvent. Preferred solvents are lower alkane
ethers and alcohols; ethyl ether and isopropyl alcohol, THF, ethyl acetate and
the like, and ideal solvents) for solvent
extraction or recrystallization procedures may be readily determined. The
products may be further purified by column
chromatography or other appropriate methods.
Salt Formation
Also described above, in a general fashion, is a process far the formation of
acyl halides, esters or
carboxamide groups from the benzoic acid carboxyl group as well as acid or
base addition salts. In particular the
mineral acid additions salts of the carboxyl group, such as the hydrochloride
salt or hydrobromide salt, are envisioned.
Other salts may be readily envisioned.
Coupling Reaction of the Hydrochloride Salt Intermediate Compounds
The above compounds produced according to the above invention may be isolated
and further reacted to
substitute a desired group for the hydroxyl portion of the carboxyl moiety or
for one or more of the hydrogen atoms on
the phenyl or aryl ring by a coupling reaction with the desired group.
Particularly preferred is a coupling reaction an
amino group on a chroman, chromone, thiochroman, thiochromone, quinoline,
isoquinoline, which has a lipophilic moiety
or another carbamimidoyl substituent directly or indirectly attached.. For
example, 5-cyano-thiophene 2-carboxylic acid
derivatives (or an acid halide such as the acid chloride) which are made by
the procedures set forth in one of reaction
Schemes I-V, may be coupled to a hydrochloride salt of the amino group on an
amino chromone to farm 5-(5-cyano-2-
thiophenoyl)-aminochromone derivatives, or other similar heteroaroyl or aroyl
derivatives, which are known platelet
aggregation inhibitors. For an example of such a platelet aggregation
inhibitor having the 5-cyano-2-thiophenoyl-amino
side group attached to a bicyclic core structure see U.S. Patent 5,731,324, at
pages 35-36, compound (LX). The ring
portion of the above cyano-amyl or cyano-heteroaroyl derivatives may be
substituted by groups such as methyl, ethyl,
fluoro, iodo, bromo, chloro, methoxy, ethyoxy, and the like which results in
compounds that are known platelet
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aggregation inhibitors. Standard coupling procedures may be utilized, but
procedures utilizing reaction mixtures
wherein oxalyl chloride, toluene, DMi=, pyridine and methylcyanide, or the
like, are present are preferred for the
coupling reaction. The resulting hydrochloridL salt may be utilized or
converted to the free base, which may itself be
utilized or converted to salts of various inorganic and organic acids and
bases. The production of such salts is within
the scope of this invention. The free base or salts may be purified by various
techniques such as recrystallization in a
lower alkanol such as methanol, ethanol, propanol, isopropanol and the like,
for example, or a mixture thereof.
Preferably, the compound is recovered as the hydrochloride salt with an
appropriate recrystallization. Non-toxic and
physiologically compatible salts are particularly useful although other less
desirable salts may have use in the
processes of isolation and purification.
The compounds made by coupling an appropriate amino-substituted bicyclic
structure with the cyanobenzoic
acids produced according to the above invention, selected and used as
disclosed herein or by reference, 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 occurring post-thrombolytic
therapy or post-coronary angioplasty, (b)
the treatment or prevention of any thrombotically mediated cerebravascular
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 associated with multi-organ failure or not), thrombotic
thrombocytopenic purpura,
thromboanginitis obliterans, or thrombotic disease associated with heparin
induced thrombocytopenia, (e) the
treatment or prevention of thrombotic complications associated with
extracorpareal 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, intro-aortic balloon
pump, coronary stent or cardiac valvel, 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 intermediates
according to the present invention can be
used to make compounds that can be added to or contacted with any medium
containing or suspected to contain
factor Xa and in which it is desired that blood 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.
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Without further description, it is believed that one of ordinary skill in the
art can, using the preceding
description, fully practice the invention as set forth above and in the
following claims. The preferred embodiments
detailed above are non-limiting in that one of ordinary skill in view of the
above will readily envision other permutations
and variations on the invention without departing from the principal concepts
and spirit of the invention. Such
permutations and variations are also within the scope of the present
invention.
13
