The invention related to pyrrolo-naphthyl acids as pai-1 inhibitors
BACKGROUND
The present invention relates generally to pyrrolo-napthyl acids, such as pyrrolo-
5-yJ-naphthyl]oxyalkyl-acids, and methods of using them.
The serine protease inhibitor PAI-1 is one of the primary inhibitors of the
fibrinolytic system. The fibrinolytic system includes the proenzyme plasminogen, which is
converted to the active enzyme, plasmin, by one of two tissue type plasminogen activators, /-PA
orw-PA. PAI-1 is the principal physiological inhibitor of /-PA and u-PA? One of plasmin's
main functions in the fibrinolytic system is to digest fibrin at the site of vascular injury. The
fibrinolytic system, however, is not only responsible for the removal of fibrin from circulation
but is also involved in several other biological processes including ovulation, embryogenesis,
intima proliferation, angiogenesis, tumorigenesis, and atherosclerosis.
Elevated levels of PAJ-I have been associated with a variety of diseases and
conditions including those associated with impairment of the fibrinolytic system. For example,
elevated levels of PAJ-I have been implicated in thrombotic diseases, e.g., diseases characterized
by formation of a thrombus that obstructs vascular blood flow locally or detaches and embolizes
to occlude blood flow downstream. (Krishnamurti, Blood, 6.9, 798 (1987); Reilly,
Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigation,
92, 2756 (1993), Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)).
Antibody neutralization of PAI-1 activity resulted in promotion of endogenous thrombolysis and
reperfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation 85, 305, (1992)).
*
Elevated levels of PAI-1 have also been implicated in diseases such as polycystic ovary
syndrome (Nordt, Journal of clinical Endocrinology and Metabolism, 85, 4, 1563 (2000)), bone
loss induced by estrogen deficiency (Daci, Journal of Bone and Mineral Research, 15,8,1510
(2000)), cystic fibrosis, diabetes, chronic periodontitis, lymphomas, diseases associated with
extracellular matrix accumulation, malignancies and diseases associated with neoangiogenesis,
$i!^l^ associated with infections, and diseases associated with
increased wPA levels such as breast and ovarian cancer.
In view of the foregoing, there exists a need for inhibitors of PAI-1 activity and
methods of using them to modulate PAI-1 expression or activity, for example, in treating
disorders associated with elevated PAI-1 levels.
SUMMARY
In one aspect, the present invention relates to pyrrolo-naphthyl acids of the
following formula:
or solvates, hydrates or pharmaceutically acceptable salt or ester forms thereof; wherein:
Ar is aryl or heteroaryl;
RI is hydrogen, Ci-Q2 alkyl, Ce-i4 aryl, C6.i4ar(C|.6)alkyl, -(CH2)p-heteroaryl,
-(CH2)p-CO-aryl, -(CH2)p-CO-heteroaryl, -(CH2)p-CO-(Ct-C6)alkyl, C2-C7 alkenyl, C2-C7
alkynyl, or C3-Cg cycloalkyl.
R2 and R3 are independently hydrogen, C)-C]2 alkyl, Q.Haryl, C6.i4ar(Ci-6)alkyl,
-(CH2)p-heteroaryl, halogen, Ci-Ce alkoxy, aralkyl, alkoxyaryl, nitro, carboxy(Ci-Cs alkyl),
carbamide, carbamate, or C3-Cg cycloalkyl;
R4 is -CH(R0(CH2)nRs, -C(CH3)2Rs, -CH(R5)(CH2)nR, -CH(R5)C6H4R65
-CH(R5)C6H3(C02H)2j CH(R5)C6H2(CO2H)3, or an acid mimic;
R5 is hydrogen, Ci-C6 alkyl, C6-C|2 aryl, aralkyl, C3-C8 cycloalkyl, or
-(CH2)n(R7);
Re is CO2H, tetrazole, or P03H;
R7is
-N Sr. N r, N
n is from 0 to 6;
p is from 0 to 3;
b is from 0 to 6; and
a is from 0 to 6.
The present invention further provides, inter alia, methods of using pyrrolonapthyl
acids to, for example, modulate PAI-1 expression and/or activity. In certain methods, a
therapeutically effective amount of one or more compounds of the present invention is
administered to a subject to treat a PAI-1 related disorder. Examplary methods are those that
involve inhibiting PAI-1 activity in the subject, such as that associated with impairment of the
flbrinolytic system. In certain embodiments, one or more compounds of the present invention is
administered to a subject to treat thrombosis, e.g., venous thrombosis, arterial thrombosis,
cerebral thrombosis, and deep vein thrombosis, atrial fibrillation, pulmonary fibrosis,
thromboembolic complications of surgery, cardiovascular disease, e.g., myocardial ischemia,
atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis,
polycystic ovary syndrome, Alzheimer's disease, or cancer.
DETAILED DESCRIPTION
A. GENERAL OVERVIEW
The present invention provides novel compounds that preferably inhibit PAI-1
activity, processes for preparing such compounds, pharmaceutical compositions containing such
compounds, and methods for using such compounds, for example, in medical therapies.
Preferred compounds have properties that are useful for prevention and/or inhibition of a wide
variety of diseases and disorders including those involving the production and/or action of PAI-
1. These include disorders resulting from impairment of the flbrinolytic system including, but
not limited to, thrombosis, coronary heart disease, renal fibrosis, atherosclerotic plaque
formation, pulmonary disease, myocardial ischemia, atrial fibrillation, coagulation syndromes,
thromboembolic complications of surgery, peripheral arterial occlusion and pulmonary fibrosis.
Other disorders include, but are not limited to, polycystic ovary syndrome, Alzheimer's disease,
and cancer.
The terms "alkyl" and "alkylene," as used herein, whether used alone or as part of
another group, refer to substituted or unsubstituted aliphatic hydrocarbon chains, the difference
being that alkyl groups are monovalent (i.e., terminal) in nature whereas alkylene groups are
rs'!' Both include, but are not limited to, straight and branched
chains containing from 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms, unless
explicitly specified otherwise. For example, methyl, ethyl, propyl, iso'propyl, butyl, /-butyl and lbutyl
are encompassed by the term "alkyl." Specifically included within the definition of "alkyl"
are those aliphatic hydrocarbon chains that are optionally substituted. Accordingly, the alkyl
groups described herein refer to both unsubstituted or substituted groups. Representative
optional substituents include, but are not limited to, halogens, -CN, hydroxy, oxo (=O), acyloxy,
alkoxy, amino, amino substituted by one or two alkyl groups of from 1 to 6 carbon atoms,
aminoacyl, acylamino, thioalkoxy of from 1 to 6 carbon atoms, substituted thioalkoxy of from 1
to 6 carbon atoms, and trihalomethyl Preferred substituents include halogens, -CN, -OH, oxo
(=O), and amino groups.
The carbon number as used in the definitions herein refers to carbon backbone
and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy
substitutions and the like.
The term "alkenyl", as used herein, whether used alone or as part of another
group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not
limited to, straight and branched chains having 2 to about 10 carbon atoms (unless explicitly
specified othenvise) and containing at least one double bond. Preferably, the alkenyl moiety has
1 or 2 double bonds. Preferably, the alkenyl moiety has about 2 to about 7 carbon atoms. Such
alkenyl moieties can exist in the E or Z conformations and the compounds of this invention
include both conformations. Specifically included within the definition of "alkenyl" are those
aliphatic hydrocarbon chains that are optionally substituted. Accordingly, the alkenyl groups
described herein refer to both unsubstituted or substituted groups. Representative optional
substituents include, but are not limited to, halogens, -CN, hydroxy, acyloxy, alkoxy, amino,
amino substituted by one or two alkyl groups of from i to 6 carbon atoms, aminoacyl,
acylamino, thioalkoxy of from 1 to 6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbon
atoms, and trihalomethyl. Heteroatoms, such as 0 or S attached to an alkenyl should not be
attached to a carbon atom that is bonded to.a double bond. Preferred substituents include
halogens, -CN, -OH, and amino groups.
The term "alkynyl", as used herein, whether used alone or as part of another
group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not
limited to, straight and branched chains having 2 to about 10 carbon atoms (unless explicitly
specified othenvise) and containing at least one triple bond. Preferably, the alkynyl moiety has
about 2 to about 7 carbon atoms. In certain embodiments, the alkynyl can contain more than one
tripJle'lilibld.'&fdlS^ group must contain at least four carbon atoms.
Specifically included within (he definition of "alkynyl" are those aliphatic hydrocarbon chains
that are optionally substituted. Accordingly, the alkynyl groups described herein refer to both
unsubstituted or substituted groups. Representative optional substituents include, but are not
limited to, halogens, -CN, hydroxy, acyloxy, alkoxy, amino, amino substituted by one or two
alkyl groups of from 1 to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy of from 1 to
carbon atoms, substituted thioalkoxy of from 1 to 6 carbon atoms, and trihalomethyl. Preferred
substituents include halogens, -CN, -OH, and amino groups. Heteroatoms, such as O or S
attached to an alkynyl should not be attached to the carbon that, is bonded to a triple bond.
The term "cycloalkyl" as used herein, whether alone or as part of another group,
refers to a substituted or unsubstituted alicyclic hydrocarbon group having 3 to about 20 carbon
atoms (unless explicitly specified otherwise), preferably 3 to about 6 carbon atoms. Specifically
included within the definition of "cycloalkyl" are those alicyclic hydrocarbon groups that are
optionally substituted. Accordingly, the cycloalkyl groups described herein refer to both
unsubstituted or substituted groups. Representative optional substituents include, but are not
limited to, hydroxy, oxo (=O), acyloxy, alkoxy, amino, amino substituted by one or two alkyl
groups of from 1 to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy of from 1 to 6 carbon
atoms, substituted thioalkoxy of from 1 to 6 carbon atoms, and trihalomethyl.
The term "aryl", as used herein, whether used alone or as part of another group, is
defined as a substituted or unsubstituted aromatic hydrocarbon ring group having 5 to about 50
carbon atoms (unless explicitly specified otherwise) with from about 6 to about 14 carbon atoms
being preferred, more preferably from about 6 to about 12 carbon atoms. The "aryl" group can
have a single ring-or multiple condensed rings. The term "aryl" includes, but is not limited to
phenyl, a-naphthyl, (5-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl,
biphenylenyl, and acenaphthenyl. Specifically included within the definition of "aryl" are those
aromatic groups that are optionally substituted. Accordingly, the aryl groups (e.g., phenyl,
naphthyl, and fluorenyl) described herein refer to both unsubstituted or substituted groups. In
representative embodiments of the present invention, the "aryl" groups are optionally substituted
with from 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl
of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of
2 to 6 carbon atoms, C3-C6cycloalkyl, -(CH2)p-C3-C6cycloalkyl, d-C3 perfluoroalkyl, Ci-C3
perfluoroalkoxy, -(CH2)p-phenyl, -0(CH2)p-phenyl, amino, amino substituted by one or two alkyl
groups of from 1 to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro, thioalkoxy
of from 1 to 6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbon atoms, and
rfJ&piP'ai' groups can be optionally substituted with from 1 to 3
groups selected from C|-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3-Ccycloalkyl, -(CH2)P-C3-C6
cycloalkyl, halogen, Ci-Cjperfluoroalkyl, C|-C3 perfluoroalkoxy, -(CH2)p-phenyl, and -
O(CH2)p-phenyl. In these embodiments, the phenyl group of -(CH2)p-phenyl and -O(CH2)Pphenyl
can be optionally substituted with, for example, from 1 to 3 groups selected from Ci-Ce
alkyl, C|-CC alkoxy, -(CHbVphenyl, halogen, trifluoromethyl or trifluoromethoxy. Preferred
aryl groups include phenyl and naphthyl. P is an integer from 0 to 3. Preferred substituents on
the aryl groups herein include Ci-Ce alkyl, Ci-Ce alkoxy, halo, cyano, nitro, trihalomethyl, and
Ci-Ccthio alkoxy.
As used herein, the term '.'heteroaryl", whether used alone or as part of another
group, is defined as a substituted or unsubstituted aromatic heterocyclic ring system . Heteroaryl
groups can have, for example, from about 3 to about 50 carbon atoms (unless explicitly specified
otherwise), with from about 4 about 10 being preferred. In some embodiments, heteroaryl
groups are aromatic heterocyclic ring systems having 5 to 14 ring atoms and containing carbon
atoms and 1, 2,3 or 4 oxygen, nitrogen or sulfur heteroatoms.
Representative heteroaryl groups are furan, thiophene, indole, azaindole, oxazole, thiazole,
isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazme, pyrrole, Nmethylpyrrole,
pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-
triazole, IH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran,
benzothiophene, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole,
indazole, quinazoline, quinoline, and isoquinoline. Bicyclic aromatic heteroaryl groups include
phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic
(unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered
aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered
aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one
oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic
ring having one heteroatom selected from 0, N or S. Specifically included within the definition
of "heteroaryl" are those aromatic groups that are optionally substituted. Accordingly, the
heteroaryl groups (e.g., furanyl, thiophenyl, benzofuranyl, benzothiophenyl, indolyl, pyrazolyl,
and. oxazolyl) described herein refer to both unsubstituted or substituted groups. In
representative embodiments of the present invention, the "heteroaryl" groups are optionally
substituted with from 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy,
acyl, alkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms,
alkynyl of 2 to 6 carbon atoms, C3-C6 cycloalkyl, -(CH2)p-C3-C6cycloalkyJ, CrC3 perfluoroalkyl,
i, -U(CH2)p-phenyl, ammo, ammo substituted by one or
two alkyl groups of from 1 to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro,
thioalkoxy of from 1 to 6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbon atoms, and
trihalomethyl. In some embodiments of the present invention, the "heteroaryl" groups can be
optionally substituted with from 1 to 3 groups selected from Ci-Cs alkyl, Ci-Ce alkoxy, hydroxy,
C3-C6cycloalkyl, -(CH2)P-C3-C6 cycloalkyl, halogen, Ci-Cj perfluoroalkyl, Ci-C3
perfluoroalkoxy, -(CH2)p-phenyl, and -O(CH2)p-phenyl. In these embodiments, the phenyl group
of -(CH2)p-phenyl and -O(CH2)p-phenyl can be optionally substituted with, for example, from 1
to 3 groups selected from Ci-Cg alkyl, C|-Ce alkoxy, phenyl, halogen, trifluoromethyl or
trifluoromethoxy. P is an integer of from 0 to 3. Preferred heteroaryls of the present invention
include substituted and unsubstituted furanyl, thiophenyl, benzoraranyl, benzothiophenyl,
indolyl, pyrazolyl, and oxazolyl.
The term "alkoxy" as used herein, refers to the group Ra-O- wherein R is an alkyl
group as defined above. The term "thioalkoxy" as used herein, refers to the group -O-Ra-Swherein
Ra is an alkyl group as defined above. Specifically included within the definition of
"alkoxy" and "thioalkoxy" are those groups that are optionally substituted. Accordingly, the
alkoxy and thioalkoxy groups described herein refer to both unsubstituted or substituted groups.
Preferred substituents on alkoxy and thioalkoxy groups include halogens, -CN, -OH, and amino
groups.
The term "alkoxyaryl" as used herein, refers to the group Ra-O-aryl- wherein Ra is
an alkyl group as defined above and aryl is as defined above. '
The term "arylalkyl" or "aralkyl" refers to the group -Ra-Rb, where R* is an
alkylene group as defined above, substituted by R&, an aryl group,. Preferred aralkyl groups
include C6-uar(Ci-6)alkyl groups. Aralkyl groups of the present invention are optionally
substituted. For example, in preferred embodiments, the benzyl groups of the present invention
are optionally substituted with from 1 to 3 groups selected from CrC6 alkyl, Cj-Cg alkoxy,
hydroxy, C3-C6 cycloalkyl, -(CH2)P-C3-C6cycloalkyl, halogen, Ci-C3 perfluoroalkyl, C)-C3
perfluoroalkoxy, -(CH2)p-phenyl, and -O(CH2)p-phenyl. Examples of arylalkyl moieties include,
' but are not limited to, benzyl, l-pheny!ethyl, 2-phenyIethyl, 3-phenylpropyl, 2-phenylpropyl and
the like.
The term "perfluoroalkyl", as used herein, whether used alone or as part of
another group, refers to a saturated aliphatic hydrocarbon having 1 to 6 carbon atoms and two or
more fluorine atoms and includes, but is not limited to, straight or branched chains, such as -CF3)
-CH2CF3, -CF2CF3 and -CH(CF3)2.
term "halogen" oV"halo" refers to chlorine, bromine, fluorine, and iodine.
The term "carbamide," as used herein, refers to the group -C(O)NR'R" where R'
and R" are independently hydrogen, alkyl, ary] or cycloalkyl as defined herein.
The term "carbaniate," as used herein, refers to the group -OC(O)NR'R" where R'
and R" are independently hydrogen, alkyl, aryl or cycloalkyl where as defined herein.
The term "acyl" refers to a radical of the formula RC(O)-, where R is hydrogen,
alkyl, ary], or cycloalkyl as defined herein. Suitable acyl radicals include formyl, a.cetyl,
propionyl, and the like.
The term "acyloxy" refers to radicals of the formula RC(O)O-, where R is
hydrogen, alkyl, aryl or cycloalkyl as defined herein. Suitable acyloxy radicals
include CH3COO-, CH3CH2COO-, benzoyloxy, and the like.
The term "acylamino" refers to radicals of the formula RC(O)NH- where R is
hydrogen, alkyl, aryl, or cycloalkyl as defined herein.
The term "aminoacyl" refers to radicals of the formula -(R)o-3C(O)NH2 where R
is alkylene as previously described.
The term "treating" or "treatment" refers to any indicia of success in amelioration
of an injury, pathology, or condition, including any objective or subjective parameter such as
abatement; remission; diminishing of symptoms or making the injury, pathology, or condition
more tolerable to the patient; slowing in the rate of degeneration or decline; making the final
point of degeneration less debilitating; or improving a subject's physical or mental well-being.
The treatment or amelioration of symptoms can be based on objective or subjective parameters;
including the results of a physical examination, neurological examination, and/or psychiatric
evaluation. "Treating" or "treatment of a PAI-1 related disorder" includes preventing the onset
of symptoms in a subject that may be predisposed to a PAI-1 related disorder but does not yet
experience or exhibit symptoms of the disorder (prophylactic treatment), inhibiting the
symptoms of the disorder (slowing or arresting its development), providing relief from the
symptoms or side-effects of the disorder (including palliative treatment), and/or relieving the
symptoms of the disorder (causing regression). Accordingly, the term "treating" includes the
administration of the compounds or agents of the present invention to a subject to prevent or
delay, to alleviate, or to arrest or inhibit development of the symptoms'or conditions associated
with PAI-1 related disorders, e.g., tumor growth associated with cancer. A skilled medical
practitioner will know how to use standard methods to determine whether a patient is suffering
from a disease associated with enhanced levels and/or activity of PAI-1, e.g., by examining the
patient and determining whether the patient is suffering from a disease known to be associated
with "elevated PAI-Tle'vels of acfivify'br by assaying for PAI-1 levels in blood plasma or lissue
of the individual suspected of suffering from a PAI-1 related disease and comparing PAI-1 levels
in the blood plasma or tissue of the individual suspected of suffering from a PAI-1 related
disease to PAI-1 levels in the blood plasma or tissue of a healthy individual. Methods known in
the art for the detection of nucleic acids and proteins can be used for determining PAI-1 levels in
a subject, e.g., PCR, northern and Southern blots, dot blots, nucleic acid arrays, western blots,
immunoassays such as iminunoprecipitation, ELISA, proteomics assays, and the like. Increased
PAI-1 levels are indicative of disease.
In healthy individuals, PAI-1 is found at low levels in the plasma {e.g., 5-10
ng/mL), but it is elevated significantly in a number of diseases, including, for example,
atherosclerosis (Schneiderman J. et. al, Proc NatlAcad Sci 89: 6998-7002, 1992) deep vein
thrombosis (Juhan-Vague I, et. al, Thromb Haemost 57: 67-72, 1987), and non-insulin dependent
diabetes mellitus (Juhan-Vague I, et. al, Thromb Haemost 78: 565-660, 1997). PAI-1 stabilizes
both arterial and venous thrombi, contributing respectively to coronary arterial occlusion in postmyocardial
infarction (Hamsten A, et. al. Lancet 2:3-9,1987), and venous thrombosis following
post-operative recovery from orthopedic surgery. (Siemens HJ, et. al, J Clin Anesthesia 11: 622-
629, 1999). Plasma PAI-1 is also elevated, for example, in postmenopausal women, and has
! been proposed to contribute to the increased incidence of cardiovascular disease in this
population (Koh K et. al, NEnglJMed336: 683-690,1997).
The term "PAI-1 related disorder or disease" refers to any disease or condition
that is associated with increased or enhanced expression or activity of PAI-1 or increased or
enhanced expression or activity of a gene encoding PAI-1. Examples of such increased activity
or expression include the following: activity of the protein or expression of the gene encoding
the protein is increased above the level of that in normal subjects; activity of the protein or
expression of the gene encoding the protein is in an organ, tissue or cell where it is not normally
detected in normal subjects (i.e. spatial distribution of the protein or expression of the gene
encoding the protein is altered); activity of the protein or expression of the gene encoding the
protein is increased when activity of the protein or expression of the gene encoding the protein is
present in an organ, tissue or cell for a longer period than in a normal subjects (i.e., duration of
activity of the protein or expression of the gene encoding the protein is increased). A normal
' subject is a subject not suffering from a PAI-1 related disorder or disease.
The term "pharmaceutically acceptable excipient" means an excipient that is
useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable,
and includes excipients that are acceptable for veterinary use as well as for human
pharmaceutical use. Such excipieh'fs can be solid, liquid, semisolid, or, in llic case of an aerosol
composition, gaseous.
"Pharmaceutically acceptable salts and esters" refers to salts and esters that are
pharmaceutically acceptable and have the desired pharmacological properties. Such salts
include, for example, salts that can be formed where acidic protons present in the compounds are
capable of reacting with inorganic or organic bases. Suitable inorganic salts include, for
example, those formed with the alkali metals or alkaline earth metals, e.g. sodium and potassium,
magnesium, calcium, and aluminum. Suitable organic salts include, for example, those formed
with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine,
tromethamine, N-methylglucamine, and the like, Pharmaceutically acceptable salts can also
include acid addition salts formed from the reaction of amine moieties in the parent compound
with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic
acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic
acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from
carboxy, sulfonyloxy, and phosphonoxy groups present in the compounds, e.g. C\.& alkyl esters.
When there are two acidic groups present, a pharmaceutically acceptable salt or
ester can be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly where there are
more than two acidic groups present, some or all of such groups can be salified or esterified.
1 Compounds of the invention can be present in unsalified or unesterified form, or in salified
and/or esterified form, and the naming of such compounds is intended to include both the
original (unsalified and unesterified) compound and its pharmaceutically acceptable salts and
esters. Also, certain compounds can be present in more than one stereoisomeric form, and the
naming of such compounds is intended to include all single stereoisomers and all mixtures
(whether racemic or otherwise) of such stereoisomers.
The terms "inhibitor," "activator," and "modulator" as used in connection with
expression or activity refer to inhibitory, activating, or modulating molecules, respectively.
Inhibitors of the present invention include compounds or compositions that inhibit expression of
PAI-1 or bind to, partially or totally block stimulation, decrease, prevent, delay activation,
inactivate, desensitize, or down regulate the activity of PAI-1. Samples or assays comprising
PAI-1 can be treated with a composition of the present invention and compared to control
samples without a composition of the present invention. Control samples (untreated with
compositions of the present invention) can be assigned a relative activity value of 100%. In
certain embodiments, inhibition of PAI-1 is achieved when the activity value relative to the
control is about 80% or less, optionally 50% or 25, 10%, 5% or 1%.
Trie terms "pnarmaceutically acceptable", "physiologically tolerable" and
grammatical variations thereof, as they refer to compositions, earners, diluents and reagents, are
used interchangeably and represent that the materials are capable of administration to or upon a
human without the production of undesirable physiological effects such as nausea, dizziness,
gastric upset and the like which would be to a degree that would prohibit administration of the
compound.
A "therapeutically effective amount" or "pharmaceutically effective amount"
means an amount that, when administered to a subject for treating a disease, is sufficient to effect
treatment for that disease.
Except when noted, the terms "subject" or "patient" are used interchangeably and
refer to mammals such as human patients and non-human primates, as well as experimental
animals such as rabbits, rats, and mice, and other animals. Accordingly, the term "subject" or
"patient" as used herein means any mammalian patient or subject to which the compounds of the
invention can be administered. In an exemplary embodiment of the present invention, to identify
subject patients for treatment according to the methods of the invention, accepted screening
methods are employed to determine risk factors associated with a targeted or suspected disease
or condition or to determine the status of an existing disease or condition in a subject. These
screening methods include, for example, conventional work-ups to determine risk factors that
may be associated with the targeted or suspected disease or condition. These and other routine
methods allow the clinician to select patients in need of therapy using the methods and
formulations of the present invention.
When any variable occurs more than one time in any constituent or in any
formula, its definition in each occurrence is independent of its definition at every other
occurrence. Combinations of substituents and/or variables are permissible only if such
combinations result in stable compounds.
B. PYRROLO-NAPHTHYL ACIDS
As noted above, the compounds of the present invention include those of the
or solvates, hydrates or pharmaceutically acceptable salt or ester forms thereof; wherein:
AT is aryl or heteroaryl;
R, is hydrogen, Ci-Ci2 alkyl, C6-i4 aryl, C&-uar(C|.6)alkyl, -(CH2)p-heteroaryl,
-(CH2)p-CO-aryU -(CH2)p-CO-heteroaryl, -(CH2)p-CO-(Ci-C6)alkyl, aralkyl, C2-C7 alkenyl, C2-
C7 alkynyl, or C3-C8 cycloalkyl;
R2 and R3 are independently hydrogen, C|-CJ2 alkyl, CJ-M aryl, Qs-waCi-fiJalkyl,
-(CHj)p-heteroaryl, halogen, Ci-Ce alkoxy, alkoxyaryl, nitro, carboxy(Ct-Ce alkyl), carbamide,
carbamate, or C3-Ca cycloalkyl;
R4 is -CH(R6)(CH2)nR5, -CCCHa) -CH(R5)(CH2)nR6j -CH(R5)C6H4R6,
-CH(R5)C6H3(CO2H)2, CH(Ri)C6H2(C02H)3, or an acid mimic;
RS is hydrogen, C\-C6 alkyl, Ce-C|2 aryl, aralkyl, C3-Cg cycloalkyl, or
-(CH2)a(R7);
In certain embodiments in the definition of RI, R2 and R3 said Ci-Ci2 alkyl is
unsubstituted C|-C)2 alkyl or Ci-C3 perfluoroalkyl and said Ci-C6 alkoxy is unsubstiruted Ci-
alkoxy or Ci-C3 perfluoroalkoxy.
Such pyrrolo-naphthyl acids include the following compounds:
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof; wherein:
Ar, RI to Ry, b, n and p are as defined above and Rg, R&, RIO, RU and RIZ are
• j ; '
independently hydrogen, Ci-Cs alkyl, Ci-Ce alkoxy, C6-i4ar(C].6)alkyl, hydroxy, Cs-Cs
cycloalkyl, -(CH2)p-C3-C$cycloalkyl, halogen, -(CHjJp-phenyl, or -0(CH2)p-phenyl. In certain
embodiments said Ci-Ce alkyl is unsubstituted Ci-Ce alkyl or Cj-Cj perfluoroalkyl; said Ci-Cg
alkoxy is unsubstituted Ci-Ce alkoxy or Ci-Cs perfluoroalkoxy. In preferred compounds, Rg, Rg,
RIO, RU and RU are hydrogen.
In exemplary embodiments of Formulas 1, 2, 3, 4 or 5 the definitions have one or
more, e.g. all, of the following values:
RI is hydrogen, C\-C$ alkyl or -(CH2)p-phenyl;
R2 and R3 are independently hydrogen, unsubstituted Ci-Ce alkyl, phenyl-(CH2)p-,
halogen or Ci-C3 perfluoroalkyl;
R4 is -CHR5CO2H, -CH2RSC6H4CO2H, -CH2R5C6H3(CO2H)2, -CH2-tetrazole or
an acid mimic;
R5 is hydrogen, optionally substituted phenyl, or optionally substituted benzyl;
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.
In exemplary embodiments the definitions have one or more, e.g. all, of the
'following values:
Ar is phenyl, naphthyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl,
indolyl, pyrazolyl, oxazolyl or fluorenyl;
R] is hydrogen, Ci-Cg alkyl or -(CHaVphenyl;
R2 and R3 are independently hydrogen, unsubstituted C|-Ce alky], phenyl-(CH2)p-,
halogen or d-C3 perfluoroalkyl;
R4 is -CHR5C02H, -CHR5C6H4CO2H, -CHR5C6H3(CO2H)2, -CH2-tetrazole or
an acid mimic;
Rs is hydrogen, optionally substituted phenyl, or optionally substituted benzyl;
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.
In some compounds of the present invention, OR4 is in the 6 position relative to
the pyrrole ring (the numbering system used is shown in Formula 4).
Compounds of the present invention also include prodrugs and stereoisomers of
formulas 1-5.
In certain exemplary embodiments, RI is hydrogen, C|-C|2 alkyl, or -(CH2)Pphenyl
wherein the phenyl ring is optionally substituted with C|-C$ alkyl, Ci-Ce alkoxy, halogen,
trifluoromethyl, or trifluoromethoxy. In certain compounds, Rj is hydrogen, C|-C$ alkyl or-
(CH2)p-phenyl. For example, in some compounds, Rt is hydrogen, methyl, phenyl, benzyl or 4-
trifluoromethy Ibenzyl.
In some compounds, R2 and R3 are, independently, hydrogen, Ci-Ce alkyl,
halogen, C|-C3 perfluoroalkyl, or -(CH2)p-phenyl wherein the phenyl ring is optionally
substituted with Cj-Ce alkyl, Ci-Q alkoxy, halogen, trifluoromethyl, or trifluoromethoxy. In
certain embodiments of the present invention, R2 is hydrogen and R3 is hyarogen or halogen.
For example R3 is hydrogen or bromine.
CH(R5)C6H3(C02H)2 or an acid mimic. In certain embodiments, Rj is unsubstituted CH2COOH,
substituted CH2COOH, -CH2-tetrazole or -CH(R5)C6H4CO2H. In some embodiments, for
example R is unsubstituted CH2COOH; CH2COOH wherein the methylene group is substituted
with benzyl; -CH2-tetrazole; or -CH(R5)C6H4C02H.
In some compounds of the present invention, R5 is hydrogen, phenyl or benzyl.
In some exemplary embodiments, Ar is substituted or unsubstituted phenyl,
naphthyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl, indolyl, pyrazolyl, oxazolyl or
fluorenyl. In certain embodiments, Ar is a substituted or unsubstituted phenyl.
Exemplary pyrrolo-napthyl acids of the present invention include, but are not
limited to, 3-phenyl-2-{[6-(5-phenyl-lH-pyrrol-2-yl)-2-naphthyl]oxy}propanoic acid or a
pharmaceutically acceptable salt or ester form thereof; 2-{[6-(l-benzyl-5-phenyl-l//-pyrrol-2-
yl)-2-naphthyl]oxy}-3-phenylpropanoic acid or a pharmaceutically acceptable salt or ester form
thereof; 5-({[6-(5-phenyl-l/7-pyrrol-2-yl)-2-naphthyl3oxy}methyl)-l/f-tetraazole or a
pharmaceutically acceptable salt or ester form thereof; 5-({[6-(l-benzyl-5-phenyl-l//-pyrrol-2-
yl)-2-naphthyl]oxy}methyl)- l//-tetraazole or a pharmaceutically acceptable salt or ester form
thereof; 5-({[6-(l-methyl-5-phenyl-l/f-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-l//-tetraazole or a
pharmaceutically acceptable salt or ester form thereof; {[6-(l-benzyl-5-phenyl-l//-pyrrol-2-yl)-
2-naphthyl]oxy}acetic acid or a pharmaceutically acceptable salt or ester form thereof; 2-{[6-(lmethyI-
5-phenyl-l#-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid or a pharmaceuticall>
acceptable salt or ester form thereof; 3-phenyl-2-[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-
l/f-pyrrol-2-yl}-2-naphthyl)oxy]propanoic acid or a pharmaceutically acceptable salt or ester
form thereof; 5-{[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l/:f-pyrrol-2-yl}-2-
naphthyl)oxy]methyl}-l//-tetraazole or a pharmaceutically acceptable salt or ester form thereof;
[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthyl)oxy]acetic acid or a
pharmaceutically acceptable salt or ester form thereof; 5-({[6-(l,5-diphenyl-i//-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)-!#-tetraazole or a pharmaceutically acceptable salt or ester form thereof;
{[6-(l,5-diphenyl-l/f-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid or a pharmaceutically acceptable
salt or ester form thereof; 2-{[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}-3-
phenylpropanoic acid or a pharmaceutically acceptable salt or ester form thereof, 4-{[(6-{5-
phenyI-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yI}-2-naphthyl)oxy]methyl}benzoic acid or a
pharmaceutically acceptable salt or ester form thereof; 4-({[6-(l,5-diphenyl-l#-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)benzoic acid or a pharmaceutically acceptable salt or ester form thereof; 4-
{[(6- {5-phenyl-1 -[4-(tri fluoromethy l)benzyl]- l//-pyrrol-2-yl} -2-
a&opiGi[l!lS-afci!?'or a pharmaceutically acceptable salt or ester form
^hereof; 4-({[6-(5-phenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalic acid or a
pharmaceutically acceptable salt or ester form thereof.
The present invention also provides compositions comprising the pyrrolonaphthyl
acids of the present invention, including those compounds of formulas 1-5 or a
stereoisomer or pharmaceutically acceptable solvate, hydrate, salt or ester form thereof, and one
or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions include
»
pharmaceutical compositions for treating or controlling disease states or conditions associated
with increased PAI-1 activity. In certain embodiments, the compositions comprise mixtures of
one or more pyrrolo-naphthyl acids.
Certain of the compounds of formulas 1-5 contain stereogenic carbon atoms or
other chiral elements and thus give rise to stereoisomers, including enantiomers and
diastereomers. The present invention includes all of the stereoisomers of formulas 1-5, as well as
mixtures of the stereoisomers. Throughout this application, the name of the product, where the
absolute configuration of an asymmetric center is not indicated, is intended to embrace the -
individual stereoisomers as well as mixtures of stereoisomers.
Where an enantiomer is preferred, it can, in some embodiments, be provided
substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the
corresponding enantiomer refers to a compound that is isolated or separated via separation
techniques or prepared free of the corresponding enantiomer. "Substantially free," as used
herein, means that the cpmpound is made up of a significantly greater proportion of one
enantiomer. In preferred embodiments, the compound is made up of at least about 90% by
weight of a preferred enantiomer. In other embodiments of the invention, the compound is made
up of at least about 99% by weight of a preferred enantiomer. Preferred enantiomers can be
isolated from racemic mixtures by any method known to those skilled in the art, including high
performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts,
or preferred enantiomers can be prepared by methods described herein. Methods for the
preparation of preferred enantiomers are described, for example, in Jacques, et al., Enantiomers,
Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al,
4*
Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill,
NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L.
Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
Exemplary salt forms of the compounds herein include, but are not limited to,
sodium salts and potassium salts. Other exemplary salt forms of these compounds include, but
acceptable inorganic and organic bases or
Jfeids known in the art. The acids include, for example, acetic, propionic, lactic, citric, tartaric,
succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic,
phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this
invention contains a basic moiety. Salt forms prepared using inorganic bases include
hydroxides, carbonates or bicarbonates of the therapeutically acceptable alkali metals, or alkaline
earth metals, such as sodium potassium, magnesium, calcium and the like. Acceptable organic
bases include amines, such as benzylamine, mono-, di- and trialkylamines, preferably those
having alkyl groups of from 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such as
inethylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, mono-,
di-, and triethanolamine. Exemplary salts also include alkylene di amines containing up to 6
carbon atoms, such as hexamethylenediamine; cyclic saturated or unsaturated bases containing
up to 6 carbon atoms, including pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl
and N-hydroxyalkyl derivatives, such as N-methyl-morpholine and N-(2-hydroxyethyl)-
piperidine, or pyridine. Quaternary salts can also be formed, such as tetralkyl forms, such as
tetramethyl forms, alkyl-alkanol forms, such as methyl-triethanol or trimethyl-monoethanol
forms, and cyclic ammonium salt forms, such as N-methylpyridinium, N-methyl-N-(2-
hydroxyethyl)-moipholinium, N,N-di-methylmorpholinium, N-methyl-N-(2-hydroxyethyl)-
morpholinium, or N,N-dimethyl-piperidinium salt forms. These salt forms can be prepared using
the acidic compound(s) of Formulas 1-2 and procedures known in the art.
Exemplary ester forms of the compounds of this invention include, but are not
limited to, straight chain alkyl esters having from 1 to 6 carbon atoms or branched chain alkyl groups containing 1 to 6 carbon atoms, including methyl, ethyl, propyl, butyl, 2-methylpropyl
and 1,1-dimethylethyl esters, cycloalkyl esters, alkylaryl esters, benzyl esters, and the like.
Other exemplary esters include, but are not limited to, those of the formula -COORu wherein
selected from hydrogen, alkyl of from 1 to 10
olfrbon atoms, aryl of 6 to 12 carbon atoms, arylalkyl of from 6 to 12 carbon atoms; heteroaryl or
alkylheteroaryl wherein the heteroaryl ring is bound by an alkyl chain of from 1 to 6 carbon
atoms.
Acids and acid mimics, according to the invention, are defined as proton or
hydrogen donating groups. Exemplary acid mimics or mimetics of the present invention include
pharmaceutically useful carboxylic acids and acid mimics or mimetics known in the atj, such as
those described in R. Silverman, The Organic Chemistry of Drug Design and Drug Action,
Academic Press (1992) and others. Exemplary acid mimics or mimetics include, but are not
limited to the following examples, tetrazole, tetronic acid or groups having the formula:
wherein Rig is Ci-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, -CH2-(C3-C6 cycloalkyl), C3-C6
cycloalkenyl, -CH2-(C3-Ce cycloalkenyl), optionally substituted aryl or heteroaryl groups or
optionally substituted aryl(Ci-C6)alkyl or heteroaryl(Ci-C6)alkyl, with the aryl and heteroaryl
'groups as defined herein.
Is-'Sf the present invention inhibit PAI-1 activity.
Accordingly, the compounds can be used for the treatment, including prevention, inhibition,
and/or amelioration of PAI-1 related disorders in a subject, including, for example, in the
treatment of noninsulin dependent diabetes mellitus, in the treatment of cardiovascular disease,
and in the treatment of thrombotic events including those associated with coronary artery and
cerebrovascular disease. Using the methods of the present invention, a skilled medical
practitioner will know how to administer the compounds of the present invention, including
those represented by formulas 1-5, to a subject suffering from any of the diseases associated with
increased PAI-1 activity or expression, e.g., diabetes or cardiovascular disease, in order to effect
treatment for that disease.
In one exemplary embodiment, the compounds of the present invention are
administered to a subject in order to treat disease processes involving thrombotic and
prothrombotic states which include, but are not limited to, formation of atherosclerotic plaques,
venous and arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis,
• coagulation syndromes, pulmonary thrombosis, cerebral thrombosis, thromboembolic
complications of surgery (such as joint or hip replacement), and peripheral arterial occlusion.
Any disease or condition that is associated with increased PAI-1 activity or
expression in a subject can be treated using the compounds of the present invention. Exemplary
diseases and conditions include stroke, e.g., stroke associated with or resulting from atrial
fibrillation; diseases associated with extracellular matrix accumulation including, but not limited
to, renal fibrosis, chronic obstructive pulmonary disease, polycystic ovary syndrome, restenosis,
renovascular disease, and organ transplant rejection; diseases associated with neoangiogenesis,
including, but not limited to, diabetic retinopathy; Alzheimer's disease, e.g., by increasing or
normalizing levels of plasmin concentration in a subject; myelofibrosis with myeloid metaplasia,
e.g., by regulating stromal cell hyperplasia and increases in extracellular matrix proteins.
The compounds of the present invention can be used to treat, for example,
diabetic nephropathy and renal dialysis associated with nephropathy; malignancies or cancers,
including, but not limited to, leukemia, breast cancer and ovarian cancer; tumors, including, but
not limited to, liposarcomas and epithelial tumors; septicemia; obesity; insulin resistance;
proliferative diseases, including, but not limited to, psoriasis; conditions associated with
abnormal coagulation homeostasis; low grade vascular inflammation; cerebrovascular diseases;
hypertension; dementia; osteoporosis; arthritis; asthma; heart failure; arrhythmia; angina,
including, but not limited to, angina pectoris; atherosclerosis and sequelae; kidney failure;
multiple sclerosis; osteoporosis; osteopenia; dementia; peripheral vascular disease; peripheral
s-, microvascular diseases including, but not limited to,
nephropathy,'neuropathy, retinopathy and nephrotic syndrome; hypertension; Type I and II
diabetes and related diseases; hyperglycemia; hyperinsulinemia; malignant lesions; premalignant
lesions; gastrointestinal malignancies; coronary heart disease, including, but not limited to,
primary and secondary prevention of myocardial infarction, stable and unstable angina, primary
prevention of coronary events, and secondary prevention of cardiovascular events; and
inflammatory diseases, including, but not limited to, septic shock and the vascular damage
associated with infections.
The compounds of the present invention can also be administered to a subject in
combination with a second therapeutic agent, including, but not limited to, prothromboiytic,
fibrinolytic, and anticoagulant agents, or in conjunction with other therapies, for example,
protease inhibitor-containing highly active antiretroviral therapy (HAART) for the treatment of
diseases which originate from fibrinolytic impairment and hyper-coagulability of HIV-1 infected
patients. In certain embodiments, the compounds of the present invention can be administered in
conjunction with and/or following processes or procedures involving maintaining blood vessel
1 patency, including, but not limited to, vascular surgery, vascular graft and stent patency, organ,
tissue and cell implantation and transplantation. The compounds of the present invention can
also be used for the treatment of blood and blood products used in dialysis, blood storage in the
fluid phase, especially ex vivo platelet aggregation. The compounds of the present invention can
also be administered to a subject as a hormone replacement agent or to reduce inflammatory
markers or C-reactive protein. The compounds can be administered to improve coagulation
homeostasis, to improve endothelial function, or as a topical application for wound healing, e.g.,
the prevention of scarring. The compounds of the present invention can be administered to a
subject in order to reduce the risk of undergoing a myocardial revascularization procedure. The
present compounds can also be added to human plasma during the analysis of blood chemistry in
hospital settings to determine the fibrinolytic capacity thereof. In certain embodiments, the
compounds of the present invention can be used as imaging agents for the identification of
metastatic cancers.
C. SYNTHESIS OVERVIEW
Compounds of the present invention can be prepared by those skilled in the art of
organic synthesis employing conventional methods that utilize readily available reagents and
starting materials. Representative compounds of the present invention can be prepared using the
following synthetic schemes. The skilled practitioner will know how to make use of variants of
fes are well known in the art. In the following reaction
Mherries, the substituents are selected from the groups defined above.
In a preferred embodiment, the compounds of the present invention are
formulated as pharmaceuticals to treat diseases associated with increased PAI-1 activity, e.g., by
inhibiting PAI-1 activity in a subject.
In general, the compounds of the present invention can be administered as
pharmaceutical compositions by any method known in the art for administering therapeutic drugs
including oral, buccal, topical, systemic (e.g., transdermal, intranasal, or by suppository), or
parenteral (e.g., intramuscular, subcutaneous, or intravenous injection). Compositions can take
the form of tablets, pills, capsules, semisolids, powders, sustained release formulations,
solutions, suspensions, emulsions, syrups, elixirs, aerosols, or any other appropriate
compositions; and comprise at least one compound of this invention in combination with at least
one pharmaceutically acceptable excipient. Suitable excipients are well known to persons of
ordinary skill in the art, and they, and the methods of formulating the compositions, can be found
in such standard references as Alfonso AR: Remington's Pharmaceutical Sciences, 17th ed.,
Mack Publishing Company, Easton PA, 1985. Suitable liquid carriers, especially for injectable
solutions, include water, aqueous saline solution, aqueous dextrose solution, and glycols. In
some embodiments of the present invention, pyrrolo-napthyl acids suitable for use in the
practice of this invention will be administered either singly or in combination with at least one
other compound of this invention. Pyrrolo-napthyl acids can also be administered with at least
one other conventional therapeutic agent for the disease being treated.
Aqueous suspensions of the invention can contain pyrrolo-napthyl acids in
admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients
can include, for example, a suspending agent, such as sodium carboxymethylcellulose,
methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring
phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g.,
polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic
alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a
partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate),
or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a
hexitol anhydride (e.g., potyoxyethylene sorbitan mono-oleate). The aqueous suspension can
also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more
coloring agents, one or more flavoring agents, and one or more sweetening agents, such as
sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.
J3ri ilspensBS-BniibFformulated by suspending a pyrrolo-napthyl acids in a
vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as
liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a
palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be
preserved by the addition of an antiqxidant such as ascorbic acid. As an example of an injectable
oil vehicle, seeMinto, J. Pharmacol. Exp. Ther. 281:93-102,1997. The pharmaceutical
formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase
can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth,
naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from
fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of
these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The
emulsion can also contain sweetening agents and flavoring agents, as in the formulation of
syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring
agent. .
The compound of choice, alone or in combination with other suitable
components, can be made into aerosol formulations (i.e., they can be "nebulized") to be
administered via inhalation. Aerosol formulations can be placed into pressurized acceptable
propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
Formulations suitable for parenteral administration, such as, for example, by
intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, and
subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions,
which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation
isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile
suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and
preservatives. Among the acceptable vehicles and solvents that can be employed are water and
Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally
be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be
employed including synthetic mono- or diglycerides. In addition, fatty-acids such as oleic acid
can likewise be used in the preparation of injectables. These solutions are sterile and generally
free of undesirable matter. Where the compounds are sufficiently soluble they can be dissolved
directly in normal saline with or without the use of suitable organic solvents, such as propylene
glycol or polyethylene glycol. Dispersions of the finely divided compounds can be made-up in
cellulose solution, or in suitable oil, such as arachis oil.
rrhese formulations can be sterilized by conventional, well known sterilization techniques. The
formulations can contain phurmaceuucally acceptable auxiliary substances as required to
approximate physiological conditions such as pH adjusting and buffering agents, toxicity
adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride,
sodium lactate and the like. The concentration of pyrrolo-napthyl acids in these formulations
can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight,
and the like, in accordance with the particular mode of administration selected and the patient's
needs. For IV administration, the formulation can be a sterile injectable preparation, such as a
sterile injectable aqueous or oleaginous suspension. This suspension can be formulated
according to the known art using those suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in
a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol. The
formulations of commends can be presented in unit-dose or multi-dose sealed containers, such as
ampules and vials.
; Injection solutions and suspensions can be prepared, for example, from sterile
powders, granules, and tablets.
Compounds suitable for use in the practice of this invention can be administered
orally. The amount of a compound of the present invention in the composition can vary widely
depending on the type of composition, size of a unit dosage, kind of excipients, and other factors
well known to those of ordinary skill in the art. In general, the final composition can comprise
from, for example, 0.000001 percent by weight (% w) to 10 % w of the pyrrolo-napthyl acids,
preferably 0.00001 % w to 1 % w, with the remainder being the excipient or excipients.
Pharmaceutical formulations for oral administration can be formulated using
pharmaceutically acceptable carriers well known in the art in dosages suitable for oral
administration. Such carriers enable the pharmaceutical formulations to be formulated in unit
dosage forms as tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries,
suspensions, etc. suitable for ingestion by the patient. Formulations suitable for oral
administration can consist of (a) liquid solutions, such as an effectiv •„• amount of the packaged
nucleic acid suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or
tablets, each containing a predetermined amount of the active ingredient, as liquids, solids,
granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions.
Pharmaceutical preparations for oral use can be obtained through combination of
the compounds of the present invention with a solid excipient, optionally grinding a resulting
•anules, after adding suitable additional compounds, if
desired, to'obtain tablets or dragee cores. Suitable solid excipients are carbohydrate or protein
fillers and include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol;
starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose,
hydroxymethyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose;
and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If
desired, disintegrating or solubilizing agents can be added, such as the cross-linked polyvinyl
pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. Tablet forms can
include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, com starch,
potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium
stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents,
moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and
pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a
flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as
gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to
the active ingredient, carriers known in the art
The compounds of the present invention can also be administered in the form of
. suppositories for rectal administration of the drug. These formulations can be prepared by
mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures
but liquid^at the rectal temperatures and will therefore melt in the rectum to release the drug.
Such materials are cocoa butter and polyethylene glycols. '
The compounds of the present invention can also be administered by intranasal,
intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and
aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.
35:1187-1193,1995; Tjwa,/to«- Allergy Asthma Immunol. 75:107-111,1995).
The compounds of the present invention can be administered in sustained or
controlled release dosage forms (e.g., employing a slow release bioerodable delivery system),
including depot injections, osmotic pumps (such as the Alzet implant made by Alza), pills,
transdermal and transcutaneous (including electrotransport) patches, and the like, for prolonged
administration at a predetermined rate, preferably in unit dosage forms.suitable for single
administration of precise dosages. The compositions will typically include a conventional
pharmaceutical carrier or excipient and a compound of the invention. In addition, these
compositions can include other active agents, carriers, adjuvants, and the like.
b8BtHe!present invention can be delivered transdermally, by a
itopical route, formulated as applicator sticks,1 solutions, suspensions, emulsions, gels, creams,
ointments, pastes, jellies, paints, powders, and aerosols.
Encapsulating materials can also be employed with the compounds of the present
invention and the term "composition" is intended to include the active ingredient in combination
with an encapsulating material as a formulation, with or without other carriers. For example, the
compounds of the present invention can also be delivered as microspheres for slow release in the
body. In one embodiment, microspheres can be administered via intradermal injection of drug,
which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as
biodegradable and injectable gel formulations (see, e.g., Gao, Pharm. Res, 12:857-863,1995);
or, as microspheres for oral administration (see, e.g.t Eyles, J. Pharm. Pharmacol. 49:669-674,
1997). Both transdermal and intradermal routes afford constant delivery for weeks or months.
Cachets can also be used in the delivery of the compounds of the present invention, e.g., antiatherosclerotic
medicaments.
In another embodiment, the compounds of the present inventio^n can be delivered
by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by
employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind
to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes,
particularly where the liposome surface carries ligands specific for target cells, or are otherwise
preferentially directed to a specific organ, one can focus the delivery of the compound into the
target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,
Curr. Opin. Biotechnol. 6:698-708,1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587,1989).
In other cases, the preferred preparation can be a lyophilized powder in, for
example, 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to
5.5, that is combined with buffer prior to use.
A pharmaceutical composition of the invention can optionally contain, in addition
to pyrrolo-napthyl acids, at least one other therapeutic agent useful in the treatment of a disease
or condition associated with increased PAI-1 activity.
The pharmaceutical compositions are generally formulated as sterile, substantially
isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the
U.S. Food and Drug Administration
E. DETERMINING DOSAGE REGIMENS
tlie compositions or compounds disclosed herein can be
administered to the subject in a single bolus delivery, via continuous delivery (e.g., continuous
transdermal, mucosal, or intravenous delivery) over an extended time period, or in a repeated
administration protocol (e.g., by an hourly, daily or weekly, repeated administration protocol).
The pharmaceutical formulations of the present invention can be administered, for example, one
or more times daily, 3 times per week, or weekly. In an exemplary embodiment of the present
invention, the pharmaceutical formulations of the present invention are orally administered once
or twice daily.
In this context, a therapeutically effective dosage of the biologically active
agent(s) can include repeated doses within a prolonged treatment regimen that will yield
clinically significant results to alleviate one or more symptoms or detectable conditions
associated with increased PAI-1 activity. Determination of effective dosages in this context is
typically based on animal model studies followed up by human clinical trials and is guided by
determining effective dosages and administration protocols that significantly reduce the
occurrence.or severity of targeted exposure symptoms or conditions in the subject. Suitable
models in this regard include, for example, murine, rat, porcine, feline, non-human primate, and
other accepted animal model subjects known in the art. Alternatively, effective dosages can be
determined using in vitro models (e.g., immunologic and histopathologic assays). Using such
models, only ordinary calculations and adjustments are typically required to determine an
appropriate concentration and dose to administer a therapeutically effective amount of the
biologically active agent(s) (e.g., amounts that are inttanasally effective, transdermally effective,
intravenously effective, or intramuscularly effective to elicit a desired response). In alternative
embodiments, an "effective amount" or "therapeutically effective dose" of the biologically active
agent(s) will simply inhibit or enhance one or more selected biological activity(ies) correlated
with a disease or condition, as set forth above, for either therapeutic or diagnostic purposes.
The actual dosage of biologically active agents will of course vary according to
factors such as the extent of exposure and particular status of the subject (e.g., the subject's age,
size, fitness, extent of symptoms, susceptibility factors, etc), time and route of administration, as
well as other drugs or treatments being administered concurrently. Dosage regimens can be
adjusted to provide an optimum prophylactic or therapeutic response. By "therapeutically
effective dose" herein is meant a dose that produces effects for which it is administered. More
specifically, a therapeutically effective dose of the compound(s) of the invention preferably
alleviates symptoms, complications, or biochemical indicia of diseases associated with increased
PAI-1 activity. The exact dose will depend on the purpose of the treatment, and will be
asceYf&nable' By"fcnfefefcilled^MM atttising known techniques (see, e.g., Lieberman,
*** : Aarmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, 1999, The Art, Science, and
Technology of Pharmaceutical Compounding; and Pickar, 1999, Dosago Calculations). A
therapeutically effective dose is also one in which any toxic or detrimental side effects of the
active agent is outweighed in clinical terms by therapeutically beneficial effects. It is to be
further noted that for each particular subject, specific dosage regimens should be evaluated and
adjusted over lime according to the individual need and professional judgment of the prerson
administering or supervising the administration of the compounds.
In an exemplary embodiment of the present invention, unit dosage forms of the
compounds are prepared for standard administration regimens. In this way, the composition can
be subdivided readily into smaller doses at the physicians direction. For example, unit dosages
can be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form.
The active compound present in these unit dosage forms of the composition can be present in an
amount of, for example, from about one gram to about fifteen grams or more, for single or
multiple daily administration, according to the particular need of the patient. By initiating the
treatment regimen with a minimal daily dose of about one gram, the blood levels of PAI-1 and
the patients symptomatic relief analysis can be used to determine whether a larger or smaller
dose is indicated. Effective administration of the compounds of this invention can be given at an
oral dose of, for example, from about 0,1 mg/kg/day to about 1,000 mg/kg/day. Preferably,
administration will be from about 10/mg/kg/day to about 600 mg/kg/day, more preferably from
about 25 to about 200 mg/kg/day, and even more preferably from about 50 mg/kg/day to about
100 mg/kg /day. In some embodiments, a daily dosage of from about 1 mg/kg to about 250
mg/kg is provided.
The compounds of the present invention can also be solvated, especially hydrated.
Hydration can occur during manufacturing of the compounds or compositions comprising the
compounds, or the hydration can occur over time due to the hygroscopic nature of the
compounds.
In certain embodiments, the present invention is directed to prodrugs of
compounds of formulas 1-5. The term "prodrug," as used herein, means a compound that is
convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formulas 1-
Various forms of prodrugs are known in the art such as those discussed in, for example,
Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in
Enzyrnology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and
Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5,113-191
ty&rug Delivery Reviews, 8:1-38(1992), Bundgaard, J. of
Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel
Drug Delivery Systems, American Chemical Society (1975).
F. KITS
Pharmaceutical dosage forms comprising a compound of the present invention
can be placed in an appropriate container and labeled for treatment of a PAI-1 related disorder,
e.g., leukemia. Additionally, another pharmaceutical comprising at least one other therapeutic
agent useful in the treatment of the PAI-1 related disorder can be placed in the container as well
and labeled for treatment of the indicated disease. For administration of pharmaceutical dosage
forms comprising pyrrolo-napthyl acids, such labeling would include, for example, instructions
concerning the amount, frequency and method of administration. Similarly, for administration of
multiple pharmaceuticals provided in the container, such labeling would include, for example,
instructions concerning the amount, frequency and method of administration of each dosage
form.
EXAMPLES
Example 1: Synthesis of 3-pbenyI-2-{{6-(5-phenyl-l/f-pyrroI-2-yl)-2-
naphthyl]oxy}propaaoic acid.
Step 1: 2-Bromo-l-(6-methoxy-2-naphthyl)ethanone
Phenyltrimethylammoniun tribromide (9.45 g, 25.1 ramol) was added under nitrogen in portions
over approximately 2 h to a solution of l-(6-methoxy-naphthalen-2-yl)-ethanone (5.05 g,
mmol) in 50 mL of anhydrous THF at room temperature. After the addition the reaction was
stirred at room temperature for 0.5 h. and then 250 mL of cold water was added. The solid
present was collected by filtration, rinsed with 50 mL of water and dried under reduced pressure
to give 6.66g of a tan solid. Recrystallization of the solid from isopropyl alcohol gave 2-bromol-(
6-methoxy-2-naphthyl)ethanone (4.07 g, 58%) as a brown solid, mp 109-112°C. Elemental
Analysis for C,3H,iBr02 Calc'd: C, 55.94; H, 3.97; N, 0.00. Found: C, 56.03; H, 3.94; N, 0.00.
Step 2: Ethyl 2-benzoyl-4-(6-methoxy-2-naphthyl)-4-oxobutanoate NaH
(60%, 1.58 g, 35.8 mmol) was added under nitrogen in 4 equal portions over a 30-minute period
to a stirring solution of ethyl benzoylacetate (6.89 g, 35.8 mmol) in 100 mL of anhydrous DMF.
After complete addition of the NaH, the mixture was allowed to stir under nitrogen at ambient
temperature for 1 hour. After 1 hour, a solution of 2-bromo-l-(6-methoxy-2-naphthyl)ethanone
(10.0 g, 35.8 mmol), prepared in the previous step, in 100 mL of anhydrous DMF was added
fse vi-a' aff rfeSflitfqfiat'fZiin^'bcfdition funnel. Total addition time was approximately 1.5
f%urs. By TLC analysis (25% EtOAc/Hexane), 30 minutes after addition of the bromoketone
was complete, there was no starting material left. The reaction was slowly quenched by the
addition of IN HC1 (250 mL). The precipitate was isolated by filtration, rinsed wilh water and
set aside, giving 8.58 g of product. The filtrate was partitioned against EtOAc. The layers were
separated and the aqueous layer was extracted with two additional portions of EtOAc. The
combined extracts were washed five times with water, dried (MgSCM), filtered and the solvent
removed under reduced pressure to give a crude yellow solid. Dissolution of the solid in a
minimal amount of methylene chloride followed by precipitation of a solid by the addition of a
2x volume of EtOAc afforded 3.34 g of a white powder. Combination of the like batches gave
ethyl 2-benzoyl-4-(6-methoxy-2-naphthyl)-4-oxobutanoate (11.92 g, 85.2%) as an off-white
powder, mp 136-137°C. Elemental Analysis for CzzOs Calc'd: C, 73.83; H, 5.68; N, 0.00.
Found: C, 73.11 ;H, 5.75; N, 0.00.
Step 3: l-(6-Me£hoxy-2-naphthyIH-phenylbutane-l,4-dione. Ethyl 2-
benzoyl-4-(6-methoxy-2-naphthyl)-4-oxobutanoate (5.00 g, 12.8 mmol), prepared in the previous
step, was dissolved in 300 mL of tetrahydrofuran. After complete dissolution of the ester, IN
NaOH solution (28.2 mL, 28.2 mmol) was added to the THF solution. The mixture was heated
to gentle reflux for 24 hours, then allowed to cool back to ambient temperature. The mixture
was acidified with IN hydrochloric acid (105 mL) and allowed to stir for 15 minutes. The THF
was then removed under reduced pressure and the residue was partitioned between methylene
chloride and IN HC1. The layers were separated, and the aqueous layer was extracted two times
with methylene chloride. The combined extracts were dried (MgSOO, filtered and the solvent
removed under reduced pressure. Purification on silica gel (300 g, 200-300 mesh) using
methylene chloride as the eluent gave l-(6-methoxy-2-naphthyl)-4-phenylbutane-I,4-dione as a
white solid (1.64 g^400/0), mp 163.5-164.5°C. Elemental Analysis for C2iHi8O3 Calc'd:
79.23; H, 5.70; N, 0.00. Found: C, 79.25; H, 5.70; N, 0.00
Step 4: 2-(6-Methoxy-2-naphthvl)-5-phenyl-l#-pyrrole. A mixture of 1-(Smethoxy-
2-naphthyl)-4-phenylbutane-l,4-dione (1.00 g, 3.14 mmol), prepared in the previous
step, ammonium acetate (12.1 g, 157 mmoJ) and acetic acid (100 mL) was heated to IOO°C under
a nitrogen atmosphere for three hours. The mixture was cooled to ambient temperature, and the
precipitate was isolated by filtration to give 2-(6-methoxy-2-naphthyl)-5-phenyl-l//-pyrrole as a
white solid (0.86 g, 91%), mp 2Q8.5-209.5°C Elemental Analysis for C2|H|7NO Calc'd: C,
84.25; H, 5.72; N, 4.68. Found: C, 84.25; H, 5.77; N3 4.56.
(S^ A mixture of 2-(6-melhoxy-2-
phthyl)-5-phenyl-lH-pyrrole (0.72 g, 2.4 mmol), prepared in the previous step, and pyridine
hydrochloride (7.2 g) was heated at 200°C under a nitrogen atmosphere for 1 hour. The mixture
was cooled to ambient temperature and the solids were dissolved in IN HC1 (150 mL). The
mixture was extracted three times with methylene chloride. The combined extracts were washed
one time with water, dried (MgSC4), filtered and the solvent removed under reduced pressure to
give 6-(5-phenyl-l#-pyrrol-2-yl)-2-naphthol as a grayish solid (0.65 g, 95%), mp 209.5-
210.5°C. Elemental Analysis for C2oHi5NO Calc'd: C, 84.19; H, 5.30; N, 4.91. Found: C,
83.38; H, 5.38; N, 4.67.
Step 6: Methyl 3-phenyI-2-{[6-(5-phenyl-l#-pyrrol-2-yl)-2-
naphthyl]oxy}propanoate. A mixture of 6-(5-phenyl-l//-pyrrol-2-yl)-2-naphthol (0.300 g, 1.05
mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyIoxypropionic acid
methyl ester (0.492 g, 1.58 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in acetone (50
mL) was stirred under nitrogen at ambient temperature overnight. The acetone was removed
under reduced pressure and the residue partitioned between EtOAc and water. The layers were
separated;and the aqueous layer was extracted two times with EtOAc. The combined extracts
were dried (MgSC4), filtered and the solvent removed under reduced pressure. Purification on a
Biotage FlashElute™ system with a KP-Sil Flash 40L column (120 g Silica Gel, 60 A) using 25%
to 60% methylene chloride in hexane as the eluent gave methyl 3-phenyl-2-{[6-(5-phenyl-l//-
pyrrol-2-yl)-2-nap'hthyl]oxy}propanoate as a grayish solid (0.447 g, 95%), mp 140-141°C.
Elemental Analysis for CsoJfcsNOj Calc'd: C, 80.51; H, 5.63; N, 3.13. Found: C, 80.26; H,
5.70; N, 2.94.
Step7:3-PhenyI-2-{[6-(5-phenyI-lJ:r-pyrrol-2-yI)-2-naphthyl]oxy}propaaoic
acid. A mixture of methyl 3-phenyl-2-{[6-(5-phenyl-l/f-pyrrol-2-yl)-2-
naphthyl]oxy}propanoate (0.25 g, 0.56 mmol), prepared in the previous step, and IN NaOH (1.1
mL, 1.1 mmol) in THF (25 mL) was stirred under nitrogen at ambient temperature overnight. By
TLC analysis, starting material was still present. The mixture was heated to 60°C for two hours,
at which time no starting material remained. The mixture was cooled to ambient temperature,
acidified with IN HC1 (2 mL) and the volatiles were removed under reduced pressure (without
the application of heat). The residue was slurried with water, the solids filtered and washed with
water. The solids were dissolved in methylene chloride, the solution dried (MgSO4), filtered and
the solvent removed under reduced pressure to give the title compound as an off-white solid
"(0.22 g, 90%), mp 176-178°C. Elemental Analysis for C29H23NO3 Calc'd: C, 80.35; H, 5.35; N,
3.23. Found: C, 79.19; H, 5.31; N, 2.97.
Example 2: Synthesis of 2-{[6-(l-beuzyI-5-pheuyl-l//-pyrrol-2-yl)-2-
aapiithyl]oxy}-3-pbenylpropanoicacid.
Step 1: l-Benzyl-2-(6-methoxy-2-naphtbyl)-5-phenyl-l.//-pyrroIe. In a similar
manner as described in step 4 of Example 1, the title compound was prepared from l-(6-
methoxy-2-naphthyl)-4-phenylbutane-l,4-dione (0.300 g, 0.942 mmol), prepared in step 3 of
Example 1, and benzyl amine (0.121 g, 1.13 mmol). The crude material was dissolved in
methylene chloride and filtered through silica gel (95 g, 200-300 mesh). The solvent tfas
removed under reduced pressure to give l-benzyl-2-(6-methoxy-2-naphthyl)-5-phenyl-l/irpyrrole
as a white solid (0.32 g, 87%), mp 152-153°C. Elemental Analysis for CzgKfoNO
Calc'd: C, 86.34; H, 5.95; N, 3.60. Found: C, 85.46; H, 6.06; N, 3.58.
Step 2: 6-(l-Benzyl-5-phenyl-l/f-pyrrol-2-yl)-2-naphthol. In a similar manner
as described in step 5 of Example 1, the title compound was prepared from 1 -benzyl-
methoxy-2-naphthyl)-5-phenyl-l/f-pyrrole (0.22 g, 0.56 mmol), prepared in the previous step,
and pyridine hydrochloride (15 g) heated to 180°C under nitrogen for 3 hours. Purification on a
Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 A) using
methylene chloride as the eluent gave 6-(l-benzyl-5-phenyl-l//-pyrrol-2-yl)-2-naphthol
grayish solid (0.155 g, 73%), mp 153-154°C. Elemental Analysis for C27H2|NO Calc'd: C,
86.37; H, 5.64; N, 3.73. Found: C, 85.95; H, 5.86; N, 3.59.
Step 3: Methyl 2-{[6-(l-benzyI-5-phenyl-l//r-pyrroI-2-yl)-2-naphthyl]oxy}-3-
phenylpropanoate. In a similar manner as described in step 6 of Example 1, the title compound
was prepared from 6-(l-benzyl-5-phenyl-l#-pyrrol-2-yl)-2-naphthol (0.140 g, 0.373 mmol),
prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl
ester (0.175 g, 0.560 mmol) and cesium carbonate (0.243 g, 0.746 mmol). Purification on a
Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 A) using
20% to 50% methylene chloride in hexane as the eluent gave methyl 2-{[6-(l-benzyl-5-phenyll//-
pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.175 g, 88%), mp 57-
62°C. Elemental Analysis for C37H3|N03 Calc'd: C, 82.66; H, 5.81; N, 2.61. Found: C, 82.39;
H, 5.88; N, 2.46.
Step 4: 2-{[6-(l-Benzyl-5-phcnyl-lflr-pyrrol-2-yl)-2-naphthyl]oxy}-3-
phenylpropanoic acid. In a similar manner as described in step 7 of Example 1, the title
compound was prepared from methyl 2-{[6-(l-benzyl-5-phenyl-l//-pyrrol-2-yl)-2-
naphthyl]oxy}-3-phenylpropanoate (0.145 g, 0.270 mmol), prepared in the previous step, and the
addition of water (3 mL) to the reaction mixture. After the volatiles were removed under
reduced pressure, the residue was partitioned between water and methylene chloride. The layers
werf"separ-ated-M<3%M'1a<}ueouS'iay&r.''was extracted one time with methylene chloride. The
cabined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure
to give the title compound as an off-white solid (0.127 g, 90%), mp 70-80°C. Elemental
Analysis for C36H29N03' 0.48 H2O C.alc'd: C, 81.23; H, 5.67; N, 2.63. Found: C, 80.67; H,
6.28; N, 2.36.
Examples: Synthesis of 5-({[6-(5-phenyl-l//-pyrrol-2-yl)-2-
» naphthyl]oxy}rnethyl)-l//-tetraazole.
Step 1: {[6-(5-Phenyl-l/f-pyrroI-2-yI)-2-naphthyl]oxy}acetonitriIe. In a
similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(5-
phenyl-l/f-pyrrol-2-yl)-2-naphthol (0.285 g, 1.00 mmol), prepared in step 5 of Example 1,
bromoacetonitrile (0.144 g, 1.20 mmol) and cesium carbonate (1.63 g, 5.00 mmol) with the
exception that the reaction was complete after 2 hours at ambient temperature. The isolated tan
solids (0.323 g, 100%) were used without further purification, mp 141.5-142.5°C. Elemental
Analysis for C22H,6N2O Calc'd: C, 81.46; H, 4.97; N, 8.64. Found: C, 80.37; H, 4.93; N, 8.57.
Step 2: 5-({[6-(5-Pbenyl-l/^pyrro!-2-yI)-2-naphthyIJoxy}methyl)-l#-
tetraazole. A mixture of {(6-(5-phenyl-l//-pyrrol-2-yl)-2-naphthyI]oxy}acetonitrile (0.20 g,
0.62 mmol), prepared in the previous step, ammonium chloride (0.12 g, 1.85 mmol) and sodium
azide (0.099 g, 1.85 mmol) in DMF (10 mL) was heated at 100°C under nitrogen for 5 hours.
After cooling to ambient temperature, TLC analysis showed that starting material remained. An
additional portion each of ammonium chloride and sodium azide was added, and the mixture was
again heated at 100°C for 4 hours, at which time no starting material remained. The mixture was
cooled to ambient temperature, acidified with IN HC1 (5 mL) and diluted with water (20 mL).
The precipitated solids were isolated by vacuum filtration to give the title compound as a gray
solid (0.202 g, 89%), mp 237-240°C (dec). Elemental Analysis for C22H|7N5O • 0.55 H2O' 0.11
'C3H7NO Calc'd: C, 69.60; H, 4.94; N, 18.57. Found: C, 69.71; H, 4.64; N, 18.61.
Example 4: Synthesis of 5-({[6-(l-benzyI-5-phenyI-ltf-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)-l/f-tetraazole.
Step 1: {[6-(l-Benzyl-5-pbenyl-l#-pyrroI-2-y))-2-naphthyl]oxy}acetonitriIe.
In a similar manner as described in step 1 of Example 3, the title compound was prepared from
6-(l-benzyl-5-phenyl-l//-pyrrol-2-yl)-2-naphthol (0.250 g, 0.665 mmol), prepared in step 2 of
Example 2, bromoacetonitrile (0.096 g, 0.80 mmol) and cesium carbonate (1.08 g, 3.33 mmol)
with the exception that the reaction was complete after 70 minutes at ambient temperature. The
crude material was dissolved in methylene chloride and filtered through silica gel (45 g, 200-300
mesh). The solvent was removed under reduced pressure to give {[6-(l-benzyI-5-phenyl-17/-
as a beige solid (0.276 g, 100%), mp 156-157°C.
Analysis for C29H22N2O Calc'd: C, 84.03; H, 5.35; N, 6.76. Found: C, 83.15; H,
5.46; N, 6.54.
Step 2: 5-({[6-(l-Benzyl-5-phenyl-lJy-pyrrol-2-yl)-2-naphthylJoxy}methyl)-
]J:T-tetraazole. In a similar manner as described in step 2 of Example 3, the title compound was
prepared from {[6-(l-benzyl-5-phenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 0.48
mmol), prepared in the previous step, ammonium chloride (0.077 g, 1.44 mmol) and sodium
azide (0.094 g, 1.44 mmol) in DMF (10 mL). The solids were isolated by vacuum filtration and
dissolved in methylene chloride. The organic solution was dried (MgSC4), filtered and the
solvent removed under reduced pressure to give 5-({[6-(l-benzyl-5-phenyl-l//-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)-l//-tetraazole as an amorphous beige solid (0.203 g, 92%), mp 190-200°C
(dec). Elemental Analysis for CagH^NsO' 0.49 H2O ' 0.21 C3H7NO Calc'd: C, 73.90; H, 5.32;
N, 15.15. Found: C, 73.05, H, 5.25; N, 15.03.
Example 5: Synthesis of 5-({[6-(l-methyl-5-phenyM//-pyrroI-2-yl)-2-
naphthyl]oxy}methyl)-l//-tetraazole.
Step 1: 2-(6-Methoxy-2-uaphthyl)-l-methyl-5-phenyl-l/f-pyrroIe. In a similar
manner as described in step 4 of Example 1, the title compound was prepared from l-
methoxy-2-naphthyl)-4-phenylbutane-l,4-dione (3.00 g, 9.42 mmol), prepared in step 3 of
Example 1, and methyl amine (8 M solution in EtOH, 100 mL, 800 mmol). Isolation of the
solids by vacuum filtration gave 2-(6-methoxy-2-naphthyl)-l-methyl-5-phenyl-l#-pyrrole as a
white solid (2.5 g, 85%), mp 197-198°C. Elemental Analysis for C22H|9NO Calc'd: C, 84.31;
H, 6.11; N, 4.47. Found: C, 84.47; H, 6.08; N, 4.41.
Step 2: 6-(l-Methyl-5-phenyI-l#-pyrrol-2-yI)-2-naphthol. In a similar manner
as described in step 5 of Example 1, the title compound was prepared from 2-(6-methoxy-2-
naphthyl)-l-rnethyl-5-phenyl-l//-pyrrole (2.3 g, 7.3 mmol), prepared in the previous step, and
pyridine hydrochloride (60 g) heated at 200°C for 3 hours under a nitrogen atmosphere. The
crude material was dissolved in EtOAc and filtered through silica gel (95 g, 200-300 mesh). The
solvent was removed under reduced pressure to give 6-(l-methyl-5-phenyl-l#-pyrrol-2-yl)-2-
naphthol as a tan solid (2.0 g, 91%), mp 230-231°C. Elemental Analysis for C2|H|7NO. Calc'd:
C, 84.25; H, 5.72; N, 4.68. Found: C, 84.24; H, 5.76; N, 4.61.
Step 3: {l6-(l-MethyI-5-phenyl-lJflr-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile.
In a similar manner as described in step 1 of Example 4, the title compound was prepared from
.45 g, 1.5 mmol), prepared in the previous
ste^, bromoacetonitrile (0.216 g, 1.8 mmol) and cesium carbonate (2.45 g, 7.52 mmol) with the
exception that the reaction was complete after 100 minutes at ambient temperature. The crude
material was dissolved in methylene chloride and filtered through silica gel (45 g, 200-300
mesh). The solvent was removed under reduced pressure to give {[6-(l-methyl-5-phenyl-l//-
pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as an off-white solid (0.494 g, 97%), mp 191.5-
192.5°C. Elemental Analysis for C23Hi8N2O Calc'd: C, 81.63; H, 5.36; N, 8.28. Found: C,
81.06; H, 5.14; N, 8.04.
Step 4: 5-({[6-(l-Methyl-5-pheny!-l//-pyrroI-2-yl)-2-naphthyl]oxy}methyl)-
l//-tetraazole. In a similar manner as described in step 2 of Example 3, the title compound was
prepared from {[6-(l-methyl-5-phenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 0.48
mmol), prepared in the previous step, ammonium chloride (0.077 g, 1.44 mmol) and sodium
azide (0.094 g, 1.44 mmol) in DMF (10 mL). The precipitated solids were isolated by vacuum
filtration to give 5-({[6-(l-methyl-5-phenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-l//-
tetraazole as a white solid (0.228 g, 81%), mp 231-233°C (dec). Elemental Analysis for
C23H19NsO- 0.34 H20' 0.07 C3H7NO Calc'd: C, 70.99; H, 5.18; N, 18.08. Found: C, 70.84; H,
5.07; N, 13-18.
Example 6: Synthesis of {[6-(l-benzyI-5-phenyI-l//-pyrroI-2-yl)-2-
naphthyl]oxy}acetic acid.
Step 1: Methyl {[6-(l-benzyI-5-phenyl-l//-pyrrol-2-y!)-2-
naphthyljoxyjacetate. In a similar manner as described in step 1 of Example 4, the title
compound was prepared from 6-(l-benzyl-5-phenyl-l/f-pyrrol-2-yl)-2-naphthol (0.250 g, 0.665
mmol), prepared in step 2 of Example 2, methyl bromoacetate (0.122 g, 0.797 mmol) and cesium
carbonate (1.08 g, 3.33 mmol). The isolated tan amorphous solid (0.298 g, 100%) was used
without further purification, mp 101-102°C. Elemental Analysis for C3oH25N03 Calc'd: C
80.51; H, 5.63; N, 3.13. Found: C, 79.81; H, 5.60; N, 2.83.
Step 2: {[6Kl-Benzyl-5-phenyl-l#-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid.
A mixture of methyl {[6-(l-benzyl-5-phenyl-l/f-pyrrol-2-yl)-2-naphthyl]oxy}acetate (0.250 g,
0.559 mmol), prepared in the previous step, and IN NaOH (0.84 mL, 0.84 mmol) in 1:1:1
THF:MeOH:water (30 ml) was stirred at ambient temperature for 10 minutes. The volatiles
were removed under reduced pressure (without the application of heat). The residue was
partitioned between 0.1N HC1 and EtOAc. The layers were separated and the aqueous layer was
extracted one time with EtOAc. The combined extracts were dried (MgSO4), filtered and the
solvent removed under reduced pressure to give the title compound as a pale-yellow solid (0 23
E yjcwif mp''ilwD|-cucrucutaifjaaittij'ajs for C29rI23NO3 0.17 H2O Oalc d: C, 79.79; H,
5.3ft N. 3.21. Found: C, 79.88; H, 5.37; N, 2.96.
Example 7:' Synthesis of 2-{[6-(l-methyl-5-phenyl-l//-pyrrol-2-yl)-2-
naphthyIJoxy}-3-pbenyIpropanoic acid.
Step 1: Methyl 2-{[6-(l-methyl-5-phenyl-l/f-pyrrol-2-yl)-2-naphthyl]oxy}-3-
>
phenylpropanoate. In a similar manner as described in step 6 of Example 1, the title compound
was prepared from 6-(l-methyl-5-phenyl-]//-pyrrol-2-yl)-2-naphthol (0.300 g, 1.00 mmol),
prepared in step 2 of Example 5, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl
ester (0.469 g, 1.50 mmol) and cesium carbonate (0.653 g, 2.00 mmol) with the exception that
this reaction was complete after 4 hours at ambient temperature. Purification on a Biotage
Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 A) using 25% to 55%
methylene chloride in hexane as the eluent gave methyl 2-{[6-(l-methyl-5-phenyl-l#-pyrrol-2-
yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.437 g, 94%), mp 117-118°C.
Elemental Analysis for C3|H27NO3 Calc'd: C, 80.67; H, 5.90; N, 3.03. Found: C, 80.35; H,
6.16; N, 2.91.
Step 2: 2-{[6-(l-Methyl-5-phenyl-l/f-pyrrol-2-yl)-2-naphthyl]oxy}-3-
phenylpropanoic acid. In a similar manner as described in step 2 of Example 6, the title
compound was prepared from methyl 2-{[6-(l-methyl-5-phenyl-l//-pyrrol-2-yl)-2-
naphthyl]oxy}-3-phenylpropanoate (0.200 g, 0.433 mrnol}. prepared in the previous step, and IN
NaOH (0.65 mL, 0.65 mmol) in 1.5:1.5:1 THF:MeOH:water (40 mL) with the exception that this
reaction was complete after 18 hours (overnight) at ambient temperature. The title compound
was isolated as a pale-yellow solid (0.194 g, 100%) and used without further purification, mp
171-173°C. Elemental Analysis for C3oH2jN03' 0.05 H20 Calc'd: C, 80.35; H, 5.64; N, 3.12.
Found: C, 80.38; H, 5.67; N, 3.00.
Example 8: Synthesis of 3-phenyl-2-[(6-{5-phenyl-l-[4-
^irumoromethyl)benzyl]-lH-pyrrol-2-yl}-2-naphthyl)oxy]propanoic acid.
Step 1: 2-(6-Methoxy-2-naphthyI)-5-phenyI-l-[4-(trifIuorometbyl)benzyI]-
l/f-pyrrole. Jn a similar manner as described in step 4 of Example 1, the title compound was
prepared from l-(6-methoxy-2-naphthyl)-4-phenylbutane-l,4-dione (0.300 g, 0.942 mmol),
prepared in step 3 of Example 1, and trifluoromethylbenzyl amine (0.121 g, 1.13 mmol) with the
exception that this reaction required 4 hours of heating at 125°C. The crude material was
isolated by removal of the acetic acid under reduced pressure. The crude material was dissolved
filtered through silica gel (45 g, 200-300 mesh). The
solvent was removed under reduced pressure to give 2-(6-methoxy-2-naphthyl)-5-phenyl-
(trifluoromethyl)beri'zyl]-l//-pyrrole as an off-white amorphous solid (2.4 g, 83%), mp 94-97°C.
Elemental Analysis for Cag^FaNO Calc'd: C, 76.14; H, 4.85; N, 3.06. Found: C, 76.56; H,
5.58; N, 2.82.
Step 2: 6-{5-Pbenyl-l-[4-(trifluoromethyl)benzyl]-l/y-pyrroI-2-yI}-2
naphthol. In a similar manner as described in step 5 of Example 1, the title compound was
prepared from 2-(6-methoxy-2-naphthyl)-5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrole
(0.70 g, 1.5 mmol), prepared in the previous step, and pyridine hydrochloride (7 g) heated to
165°C under nitrogen for 12 hours. Purification on a Biotage Horizon™ system with a KP-Sil
Flash 40+M column (100 g Silica Gel, 60 A) using 50% to 90% methylene chloride in hexane as
the eluent gave 6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthol as a
reddish-brown amorphous solid (0.52 g, 77%), mp 63-66°C. Elemental Analysis for
C28H2oF3NO Calc'd: C, 75.84; H, 4.55; N, 3.16. Found: C, 75.18; H, 4.41; N, 3.13.
Step 3: Methyl 3-phenyl-2-[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l/fpyrrol-
2-yl}-2-napbthyl)oxy]propanoate. In a similar manner as described in step 1 of
Example 7, the title compound was prepared from 6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-
l//-pyrrol-2-yl}-2-naphthol (0.300 g, 0.676 mmol), prepared in the previous step, 3-phenyl-2-
trifluoromethanesulfonyloxypropionic acid methyl ester (0.317 g, 1.02 mmol) and cesium
carbonate (0.441 g, 1.35 mmol). Purification on a Biotage Horizon™ system with a KP-Sil Flash
40+M column (100 g Silica Gel, 60 A) using 25% to 65% methylene chloride in hexane as the
eluent gave methyl 3-phenyl-2-[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-
naphthyl)oxy]propanoate as an off-white amorphous solid (0.367 g, 90%), mp 50-55°C.
Elemental Analysis for CjgHsoFjNOa Calc'd: C, 75.36; H, 4.99; N, 2.31. Found: C, 75.24; H,
5.16; N, 2.22.
Step 4: 3-PhenyI-2-[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-lflr-pyrrol-2-
yI}-2-naphthyI)oxy]propanoic acid. In a similar manner as described in step 2 of Example 6,
the title compound was prepared from methyl 3-phenyl-2-[(6-{5-phenyl-l-[4-
(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthyl)oxy]propanoate (0.200 g, 0.330 mmol),
prepared in the previous step, and INNaOH (0.50 mL, 0.50 mmol) in 1.33:1.33:1
THF:MeOH:water (33 mL) with the exception that this reaction was not complete after 18 hours
(overnight) at ambient temperature. The reaction was warmed to 30°C for 1.5 hours, an
additional portion of IN NaOH (0.50 mL, 0.50 mmol) was added and the mixture maintained at
30°C for an additional 1.5 hours. The isolated yellow amorphous solid was purified by reverse-
with 0.1% formic acid as the eluent.
Isc^tion of the product from the chromatography fractions gave 3-phenyl-2-[(6-{5-phenyl-l-[4-
(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthyl)oxy]propanoic acid as a greenish
amorphous solid (0.139 g, 71%), mp 153-155°C. Elemental Analysis for CsyHfoFsNOj' 0.24
IfcO'O.lOCeHuCalc'd: C, 74.70; H, 4.98; N, 2.32. Found: C, 74.67; H, 5.23; N, 2.25.
Example 9: Synthesis of 5-{[(6-{5-PheuyI-l-[4-(trifluoromethyl)benzyI]-l#-
pyrrol-2-yl}-2-naphthyI)oxy] methyl}-17/-tetraazole.
Stejj 1: [(6-{5-Phenyl-l-[4-(trifluoromethyl)benzyI]-l//-pyrrol-2-yl}-2-
naphthyl)oxy]acetonitrile. In a similar manner as described in step 1 of Example 3, the title
compound was prepared from 6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l^-pyrrol-2-yl}-2-
naphthol (0.250 g, 0.564 mmol), prepared in step 2 of Example 8, bromoacetonitrile (0.081 g,
0.68 mmol) and cesium carbonate (0.920 g, 2.82 mmol). Purification on a Biotage FlashElute "
system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 A) using 50% methylene chloride
in hexane as the eluent gave [(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-
naphthyl)oxy]acetonitrile as a white solid (0.251 g, 92%), mp 154-155°C. Elemental Analysis
for C3oH21F3N2O- 0.10 CH2C12 Calc'd: C, 73.65; H, 4.35; N, 5.71. Found: C, 73.58; H, 4.46;
N, 5.64.
Step 2: 5-{[(6-{5-Phenyl-l-[4-(trinuoromethyI)benzyl]-l//-pyrroI-2-yl}-2-
naphthyl)oxy]methyl}-l.flr-tetraazole. In a similar manner as described in step 2 of Example 3,
the title compound was prepared from [(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-
yi}-2-naphthyl)oxy]acetonitrile (0.180 g, 0.373 mmol), prepared in the previous step, ammonium
chloride (0.060 g, 1.12 mmol) and sodium azide (0.073 g, 1.12 mmol) in DMF (10 mL). The
reaction mixture was acidified with IN HC1 (7 mL) and partitioned against methylene chloride.
The layers were separated and the aqueous layer was extracted three times with methylene
chloride. The combined extracts were dried (MgSO^, filtered and the solvent removed under
reduced pressure to give an oil. The oil contained a large amount of DMF, so it was dissolved in
EtOAc and partitioned against water. The organic layer was washed 5 times with water, dried
(MgSO4), filtered and the solvent removed under reduced pressure. The crude material was
dissolved in methylene chloride and filtered through silica gel (95 g, 200-300 mesh). The silica
gel was rinsed with one portion (500 mL) of methylene chloride and then five portions (100 mL
each) of 50% methylene chloride in hexane with 1% formic acid. The filtrate portions that
contained clean product were combined and the solvent was removed under reduced pressure to
give5-{[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrroI-2-yl}-2-naphthyl)oxy]methyl}-
l#-tetraazole as an off-white solid (0.169 g, 86%), mp 173-175°C. Elemental Analysis for
M;H, 4.26; N, 13.26. Found: C, 68.38; H, 4.03; N,
1 2 .
Example 10: Synthesis of [(6-{5-Phenyl-l-[4-(trifluoromethyl)benzyl]-l/fpyrrol-
2-yl}-2-naphthyl)oxy]acetic acid.
Step 1: Methyl [(6-{5-pheuyl-l-[4-(trifluoromethyl)benzylJ-l//-pyrrol-2-yl}-
2-naphtbyl)oxy]acetate. In a similar manner as described in step 1 of Example 3, the title
compound was prepared from 6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l#-pyrrol-2-yl}-2-
naphthol (0.250 g, 0.564 mmol), prepared in step 2 of Example 8, methyl bromoacetate (0.103 g,
0.676 mmol) and cesium carbonate (0.920 g, 2.82 mmol). Purification on a Biotage FlashElute™
system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 A) using 50% methylene chloride
in hexane as the eluent gave methyl [(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l#-pyrrol-2-
yl}-2-naphthyl)oxy]acetate as an off-white solid (0.271 g, 93%), mp 90-91°C. Elemental
Analysis for C3iH24F3NO3' 0.09 C6HM Calc'd: C, 72.39; H, 4.87; N, 2.68. Found: C, 72.26; H,
4.68; N, 2.28.
Step 2: [(6-{5-Phenyl-l-[4-(trmuoromethyl)benzyIJ-l#-pyrrol-2-yI}-2-
naphthyl)oxy] acetic acid. In a similar manner as described in step 2 of Example 6, the title
compound was prepared from methyl [(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-
yl}-2-naphthyl)oxy]acetate (0.20 g, 0.38 mmol), prepared in the previous step, and INNaOH
(0.58 mL, 0.58 mmol) in 1.67:1.67:1 THF:MeOH:water (39 mL). Purification on a Biotage
Horizon™ system with a KP-Sil Flash 25+M column (40 g Silica Gel, 60 A) using 25% EtOAc in
hexane with 1% formic acid as the eluent gave [(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l/fpyrrol-
2-yl}-2-naphthyl)oxy]acetic acid as an off-white solid (0.155g, 79%), mp 154-156°C.
Elemental Analysis for C3oH22F3N03' 0.02 H2O Calc'd: C, 71.80; H, 4.43; N, 2.79. Found: C,
71.96; H, 4.55; N, 2.61.
Example 11: Synthesis of 5-({[6-(l,5-diphenyl-l#-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)-l//-tetraazole.
Step I: 2-(6-Methoxy-2-naphthyl)-l,S-dipbenyI-l/f-pyrrole. In a similar
manner as described in step 1 of Example 8, the title compound was prepared from l-(6-
methoxy-2-naphthyl)-4-phenylbutane-l,4-dione (1.50 g, 4.71 mmol), prepared in step 3 of
Example 1, and aniline (3.07 g, 33.0 mmol). Purification on silica gel (500 g, 200-300 mesh)
using 0% to 50% methylene chloride in hexane as the eluent gave 2-(6-methoxy-2-naphthyl)-l,5-
diphenyl-l//-pyirole as an off-white solid (1.36 g, 77%), mp 199-200°C. Elemental Analysis for
C27H21NO-0.11CH2C12 Calc'd: C, 84.62; H, 5.56; N, 3.64. Found: C, 84.55; H, 5.67; N, 3.61.
$-l#-pyrrol-2-yl)-2-naphthoI. In a similar manner as
described in step 5 of Example 1, the title compound was prepared from 2-(6-mcthoxy-2-
naphthyl)-l,5-diphenyl-l//-pyrrole (1.25 g, 3.33 mmol), prepared in the previous step, and
pyridine hydrochloride (30 g) with the exception that this reaction required heating at 205°C.
Purification on silica gel (500 g, 200-300 mesh) using methylene chloride as the eluent gave 6-
(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthol as a reddish solid (1.00 g, 83%), mp 222-223°C.
Elemental Analysis for C26Hi9NO' 0.11 C4H802 Calc'd: C, 85.57; H, 5.40; N, 3.77.' Found: C,
85.28; H, 5.53; N, 3.73.
Step 3: {[6-(l,5-DiphenyI-l/f-pyrroI-2-yI)-2-naphthyl]oxy}acetonitrile. In a
similar manner as described in step 6 of Example 1, the title compound was prepared from 6-
(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthol (0.200 g, 0.553 mmol), bromoacetonitrile (0.0796 g,
0.664 mmol) and cesium carbonate (0.900 g, 2.77 mmol) with the exception that the product was
extracted with two portions each of methylene chloride and EtOAc. Purification on a Biotage
Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 A) using 55% to 95%
methylene chloride in hexane as the eluent gave {[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-
naphthyl]oxy}acetonitrile as a white solid (0.170 g, 77%), mp 229-230°C. Elemental Analysis
for C28H2oN2Cr 0.05 CH2C12 Calc'd: C, 83.24; H, 5.01; N, 6.92. Found: C, 83.12; H,
Step 4: 5-({[6-(l,5-DiphenyI-l//-pyrrol-2-yl)-2-naphthyi]oxy}methyl)-mtetraazole.
In a similar manner as described in step 2 of Example 3, the title compound was
prepared from {[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.180 g, 0.373
mmol), prepared in the previous step, ammonium chloride (0.060 g, 1.12 mmol) and sodium
azide (0.073 g;4'.12 mmol) in DMF (10 mL). The precipitated solids were isolated by vacuum
filtration to give 5-({[6-(l,5-diphenyl-l/f-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-l//-tetraazole as
an off-white solid (0.130 g, 98%), mp 269-270°C (dec). Elemental Analysis for C2gH2iN50
Calc'd: C, 75.83; H, 4.77; N, 15.79. Found: C, 75.83; H, 4.69; N, 15.50.
Example 12: Synthesis of {[6-(l,5-diphenyl-l//-pyrrol-2-yI)-2-
naphthyl]oxy}acetic acid.
Step 1: Methyl {[6-(l,5-diphenyl-l//-pyrroI-2-y!)-2-naphtbyl]oxy}acetate. In
a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-
(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthol (0.200 g, 0.553 mmol), prepared in step 2 of Example
11, methyl bromoacetate (0.102 g, 0.664 mmol) and cesium carbonate (0.900 g, 2.77 mmol) with
the exception that the product was extracted with methylene chloride. Purification on a Biotage
Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 A) using 55% to 95%
metflyJten*chl(&ftae'W^exa'liie"lSi:tlM"ement gave methyl {[6-(l,5-diphenyl-l#-pyrrol-2-yl)-2-
naphthyljoxy} acetate as an off-white solid (0.22 g, 92%), mp 188-189°C. Elemental Analysis
forC29H23N(V0.16CH2Cl2Calc'd: C, 78.34; H, 5.26; N, 3.13. Found: C, 77.73; H, 5.08; N,
3.07.
, Step 2: {[6-(l,5-Diphenyl-l//-pyrroI-2-yl)-2-naphthyl]oxy}acetic acid.. In a
similar manner as described in step 2 of Example 6, the title compound was prepared from
methyl {[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}acetate (0.17 g, 0.39 mmol), prepared
in the previous step, and IN NaOH (0.59 mL, 0.59 mmol) in 5:5:1 THF:MeOH:water (55 mL)
with the exception that this reaction required heating to 65°C and was complete after 6 hours.
The still warm reaction mixture was filtered and then allowed to cool to ambient temperature.
The mixture was acidified with IN HCI (2.5 mL) and the volatiles were removed under reduced
pressure (without the addition of heat). The resulting slurry was diluted with water (25 mL) and
the solids were isolated by filtration to give {[6-(l,5-diphenyl-l#-pyrrol-2-yl)-2-
naphthyl]oxy} acetic acid as an off-white solid (0.148 g, 90%), mp 258-260°C (dec). Elemental
Analysis for C28H21NO310.23 H2OCalc'd: C, 79.39; H, 5.11; N, 3.31. Found: C, 78.84; H,
5.03; N, 3*00.
Example 13: Synthesis of 2-{[6-(l,5-diphenyl-l/T-pyrrol-2-yl)-2-
naphthyl]oxy}-3-phenylpropanoic acid.
Step 1: Methyl 2-{[6-(l,5-diphenyl-l#-pyrro!-2-yl)-2-naphthyl]oxy}-3-
phenylpropanoate. In a similar manner as described in step 1 of Example 7, the title compound
was prepared from 6-(l,5-diphenyl-l#-pyrrol-2-yl)-2-naphthol (0.300 g, 0.676 mmol), prepared
in step 2 of Example 11, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester
(0.317 g, 1.02 mmol) and cesium carbonate (0.441 g, 1.35 mmol) with the exception that this
reaction was complete after 30 minutes at ambient temperature. Purification on a Biotage
Horizon™ system with a KP-Sil Flash 25+M column (40 g Silica Gel, 60 A) using 25% to 65%
methylene chloride in hex'ane as the eluent gave methyl 2-{[6-(l,5-diphenyl-l.#-pyrrol-2-yl)-2-
naphthyl]oxy}-3-phenylpropanoate as a white solid (0.257 g, 89%), mp 178-179°C. Elemental
Analysis for C36H29NO3 Calc'd: C, 82.58; H, 5.58; N, 2.67. Found: C; 81.87; H, 5.10; N, 2.50.
Step 2: 2-{[6-(l,5-DiphenyI-l/f-pyrroI-2-yI)-2-naphthylJoxy}-3-
phenylpropanoic acid. In a similar manner as described in step 2 of Example 12, the title
compound was prepared from methyl 2-{[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}-3-
phenylpropanoate (0.186 g, 0.355 mmol), prepared in the previous step, and INNaOH (0.53 mL,
0.53 mmol) in 2:2:1 THF:MeOH:water (25 mL). The starting material required heating to
dissolve in the THF (10 mL). After the solution was clear, MeOH (10 mL) was added followed
by tfeefwaler"(5Jif;ilP)Jt:-li)he fljatftiSh-tvd's complete after 2.5 hours. The solids were isolated by
filtration to give 2-{[6-(l,5-diphenyl-l#-pynxl-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid
as a beige solid (0.17 g, 94%), mp 194-196°C (dec). Elemental Analysis for CssNOj' 0.23
H2O Calc'd: C, 81.83; H, 5.39; N, 2.73. Found: C, 81.07; H, 5.44; N, 2.56.
Example 14: 4-{[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-lH-pyrrol-2-yl}-
2-naphthyl)oxy]methyl}benzoic acid.
Step 1: methyl 4-{[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l/7-pyrrol-2-
yI}-2-naphthyl)oxy]methyl}benzoate. A mixture of 6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-
l//-pyrrol-2-yl}-2-naphthol (250 mg, 0.564 mmol), prepared in step 2 of Example 8, methyl 4-
(bromomethyl)benzoate (155 mg, 0.677 mmol) and cesium carbonate (918 mg, 2.82 mmol) in 50
rnL of acetone was stirred under nitrogen at room temperature for 1.5 h. The reaction was
concentrated under reduced pressure to remove the acetone. The residue was partitioned
between ethyl acetate and water. The aqueous layer was separated and extracted multiple times
with ethyl acetate. The combined extracts were dried (MgSCU), filtered and the-solvent removed
under reduced pressure to give 0.36 g of a tan solid. Purification of the solid on a Biotage
Horizon™ system with a KP-SIL Flash 40+M column using 50% methylene in hexane as the
eluent gave methyl 4-{[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-
naphthyl)oxy]methyl}benzoate (260 mg, 78%) as an off-white solid, mp 154-155°C. Elemental
Analysis for CsT^sFjNOs Calc'd: C, 75.12; H, 4.77; N, 2.37. Found: C, 75.15; H, 4.63; N, 2.30.
Step 2: 4-{[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l^-pyrrol-2-yl}-2-
naphthyl)oxy]methyl}benzoic acid. A mixture of methyl 4-{[(6-{5-phenyl-l-[4-
(trifluoromethyl)benzyl]-l/f-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoate (200 mg, 0.338
mmol), prepared in the previous step, and 1 N NaOH (507 pL, 0.507 mmol) in 20 mL of THF
plus 20 mL of methanol plus 5 mL water was refluxed under nitrogen for 9 h. The reaction was
filtered and then allowed to cool to room temperature. The reaction was acidified by the addition
of 2.5 mL of 1 N HC1 and then concentrated under reduced pressure to remove the THF and
methanol. The residue was diluted with water. The solid formed was collected by filtration,
rinsed with water and dried under reduced pressure to give the title compound (186 mg, 95%) as
an off-white solid, mp 228-229°C. Elemental Analysis for CseHzeFaNOj '0.15 H20 ' 0.04 C4H8O
Calc'd: C, 74.47; H, 4.60; N, 2.40. Found: C, 74.52; H, 4.49; N, 2.68.
Example 15: 4-({[6-(l,5-diphenyI-lH-pyrroI-2-yI)-2-
naphthyl]oxy}methyl)benzoicacid.
l,5-diphenyl-l#-pyrroI-2-yI)-2-
napbthyljoxy}methyl)benzoate. A mixture of 6-(l,5-diphenyI-l//-pyrroJ-2-yI)-2-naphthol (300
mg, 0.830 mmol), prepared in step 2 of Example 11, methyl 4-(bromomethyl)benzoate (228 mg,
996 mmol) and cesium carbonate (1.38 g, 4.15 mmol) in 50 mL of acetone was stirred under
nitrogen at room temperature for 2.5 h. The reaction was concentrated under reduced pressure to
remove the acetone. The residue was partitioned between methylene chloride and water. The
aqueous layer was separated and extracted two times with methylene chloride. The combined
extracts were dried (MgSO-O filtered and the solvent removed under reduced pressure to give 486
mg of a tan solid. Purification of the solid on a Biotage Horizon"1 system with a KP-SIL Flash
40+M column using 10% to 50% methylene chloride in hexane as the eluent gave methyl 4-({[6-
(l,5-diphenyl-l#-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoate (320 mg, 76%) as a very light
red solid, mp 218-219°C. Elemental analysis for CasHzyNC^ Calc'd: C, 82.49; H, 5.34; N, 2.75.
Found: C, 81.71; H, 5.23; N, 2.64.
Step 2: 4-({[6-(l,5-diphenyI-lJ7-pyrroI-2-yl)-2-naphthyl]oxy}methyl)benzoic
acid. A mixture of methyl 4-({[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)benzoate (235 mg, 0.461 mmpl), prepared in the previous step, and 1 N
NaOH (692 jiL, 0.692 mmol) in 30 mL of THF plus 30 mL of methanol plus 5 mL of water was
refluxed under nitrogen for 7 h. The reaction was filtered, cooled to room temperature, acidified
by the addition of 2.5 mL of 1 N HC1 and then concentrated under reduced pressure to remove
the THF and methanol. The solid present was collected by filtration, rinsed with water and dried
under reduced pressure to give the title compound (225 mg, 99%) as a white solid, mp 309-
310°C. Elemental Analysis for Cs^sNOs' 0.05 C4H8O' 0.19 H2O Calc'd: C, 81.73; H, 5.17; N,
2.79. Found: C, 81.94; H, 5.02; N, 2.65.
Example 16: 4-{[(6-{5-phenyl-l-f4-(trinuoromethyl)benzyII-lH-pyrroI-2-yl}-
2-naphthyl)oxy]methyl}isophthalicacid.
Step 1: Dimethyl 4-{[(6-{5-phenyl-l-[4-(trinuoromethyl)beazyl]-lflr-pyrrol-
2-yl}-2-naphthyl)oxy]methyl}isophtbaIate. A mixture of 6-{5-phenyl-l-[4-
(trifluoromethyl)benzyl]-lH-pyrrol-2-yl}-2-naphthol (200 mg, 0.451 mmol), prepared in step 2
of Example 8, dimethyl 4-(bromomethyl)isophthalate (155 mg, 0.541 mmol) and cesium
carbonate (734 mg, 2.25 mmol) in 40 mL of acetone was stirred under nitrogen at room
temperature for 1.5 h. The reaction was concentrated under reduced pressure to remove the
acetone. The residue was partitioned between methylene chloride and water. The aqueous layer
was separated and extracted two times with methylene chloride. The combined extracts were
removed under reduced pressure to give 312 mg of a
yellow solid. Purification of the solid on a Biotage Horizon™ system with a KP-SIL Flash 40+M
column using methylene chloride in hexane to as the eluent gave dimethyl 4-{[(6-{5-phenyl-l-
[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalate (200 mg, 68%)
as an off-white solid, mp 172-174°C. Elemental analysis for Cj^soFaNOs Calc'd: C, 72.10; H,
4.65; N, 2.16. Found: C, 71.47; H, 4.22; N, 2.16.
Step 2: 4-{((6-{5-phenyl-l-[4-(trifluoromethyl)beazyI]-l/f-pyrrol-2-yl}-2-
naphthyl)oxy]methyl}isophthalic acid. A mixture of dimethyl 4-{[(6-{5-phenyl-l-[4-
(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalate (165 mg, 0.254
mmol), prepared in the previous step, and 1 N NaOH (1.52 mL, 1.52 mmol) in 30 mL of THF
plus 20 mL of methanol plus 5 mL of water was refluxed under nitrogen for 6 h. The reaction
was filtered, cooled to room temperature, acidified by the addition of 5 mL of 1 N HCI and then
concentrated under reduced pressure to remove the THF and methanol. The solid present was
collected by filtration, rinsed with water and dried under reduced pressure at 60°C to give the
title compound (148 mg, 94%) as a yellow solid, mp 250-252°C. Elemental Analysis for
C37H26F3NOs '0.18 C4H8O ' 0.34 H2O Calc'd: C, 70.71; H, 4.42; N, 2.19. Found: C, 70.65; H,
4.34; N, 2.13.
Example 17: 4-({[6-(5-pbenyI-lH-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)isophthalic acid.
Step 1: Dimethyl 4-({[6-(5-phenyl-l#-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)isophthalate. A mixture of 6-(5-phenyl-l//-pyrrol-2-yl)-2-naphthol (200
mg, 0.701 mmol), prepared in step 5 of Example 1, dimethyl 4-(bromomethyl)isophthalate (241
mg, 0.841 mmol) and cesium carbonate (1.14 g, 3.50 mmol) in 50 mL of acetone was stirred at
room temperature for 1.5 h. The reaction was concentrated under reduced pressure to remove
the acetone. The residue was partitioned between methylene chloride and water. The aqueous
layer was separated and extracted two times with methylene chloride. The combined extracts
were dried (MgSC), filtered and the solvent removed under reduced pressure to give a yellow
solid. Purification of the solid on a Biotage Horizon™ system with a KP-SIL Flash 40+M column
using a gradient of 85% methylene chloride in hexane to 100% methylene chloride as the eluent
gave dimethyl 4-( {[6-(5-phenyl- l#-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalate (280 mg,
81%) as a yellow solid, mp 203-205°C. Elemental Analysis for C3iH25NO5 '0.10 CH2C12
Calc'd: C, 74.70; H, 5.08; N, 2.80. Found: C, 74.24; H, 4.80; N, 2.76.
ac||: A mixture of dimethyl 4-({[6-(5-phenyl-l//-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)isophthalate (230 mg, 0.468 inmol), prepared in the previous step, and 1 N
NaOH (2.81 mL, 2.81 mmol) in 30 ml of THF plus 20 mL of methanol plus 5 mL of water was
refluxed under nitrogen for 7 h. The reaction was filtered, cooled to room temperature, acidified
by the addition of 5 mL of 1 N HC1 and then concentrated under reduced pressure to remove the
THF and methanol. The solid present was collected by filtration, rinsed with water and dried
under reduced pressure at 60°C to give the title compound (204 mg, 94%) as a yellow solid, mp
289-291°G. Elemental Analysis for C29H2|NO5' 0.40 C4H8O ' 0.22 H2O Calc'd: C, 74.06; H,
5.00; N, 2.82. Found: C, 73.83; H, 5.19; N, 2.70.
Example 18: Primary Screen for the PAI-1 Inhibition.
Test compounds are dissolved in DMSO at a final concentration of lOmM, then
diluted 100X in physiologic buffer. The inhibitory assay is initiated by the addition of the test
compound (1 - 100 uM final concentration, maximun DMSO concentration of 0.2%) in a pH 6,6
buffer containing 140 nM recombinant human plasminogen activator inhibitor-1 (PAI-1;
Molecular Innovations, Royal Oak, MI). Following a 1 hour incubation at room temperature, 70
nM of recombinant human tissue plasminogen activator (tPA) is added, and the combination of
the test compound, PAI-1 and tPA is incubated for an additional 30 minutes. Following the
second incubation, Spectrozyme-tPA (American Diagnostica, Greenwich, CT), a chromogenic
substrate for tPA, is added and absorbance read at 405 nm at 0 and 60 minutes. Relative PAl-1
inhibition is equal to the residual tPA activity in the presence of the test compound and PAI-1.
Control treatments include the complete inhibition of tPA by PAI-1 at the molar ratio employed
(2:1), and the absence of any effect of the test compound on tPA alone.
Example 19: Assay for determining ICso of inhibition of PAI-1.
This assay is based upon the non-SDS dissociable interaction between tPA and
active PAI-1. Assay plates are initially coated with human tPA (10 ug/ml). Test compounds of
the present invention are dissolved in DMSO at 10 mM, then diluted with physiologic buffer (pH
7.5) to a final concentration of l-50uM. Test compounds are incubated with human PAI-1 (50
ng/ml) for 15 minutes at room temperature. The tPA-coated plate is washed with a solution of
0.05% Tween 20 and 0.1% BSA, then the plate is blocked with a solution of 3% BSA. An
aliquot of thepyrrolo-naphthyl/PAI-1 solution is then added to the tPA-coated plate, incubated at
room temperature for 1 hour, and washed. Active PAI-1 bound to the plate is assessed by adding
an fiilfyuo't (jtM'-F.l-OOW-'ai'Iut'iM'Tot the 33B8 monoclonal antibody against human PAI-1, and
in^Jbating the plate at room temperature for 1 hour (Molecular Innovations, Royal Oak, MI).
The plate is again washed, and a solution of goat anti-mouse IgG-alkaline phosphatase conjugate
is added at a 1:50,000 dilution in goat serum. The plate is incubated 30 minutes at room
temperature, washed, and a solution of alkaline phosphatase substrate is added. The plate is
incubated 45 minutes at room temperature, and color development is determined at OD^jnm-
The quantitation of active PAI-1 bound to tPA at varying concentrations of the test compound is
used to determine the ICso. Results are analyzed using a logarithmic best-fit equation. The assay
sensitivity, is 5 ng/ml of human PAI-1 as determined from a standard curve ranging from 0-100
ng/ml.
The compounds of the present invention inhibited Plasminogen Activator
Inhibitor-1 as summarized in (Table Removed)

is Claimed :
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof; wherein:
Ar is aryl or heteroaryl;
RI is hydrogen, CrC|2 alkyl Ce-uaryl, C6-uar(C|.6)alkyl, -(CH2)p-heteroaryl,
-(CH2)p-CO-aryl, -(CH2)p-CO-heteroaryl, -(CH2)p-CO-(C,-C6)alkyl, C2-C7 alkenyl, C2-C7
. alkynyl, or Cj-Cg cycloalkyl;
R2 and Rj are independently hydrogen, C|-Cu alkyl, Ce-uaryl, C6-Har(Ci.6)alkyl,
-(CH2)p-heteroaryl, halogen, Ci-Qs alkoxy, aralkyl, alkoxyaryl, nitro, carboxy(CrC6 alkyl),
carbamide, carbamate, or Cs-Cg cycloalkyl;
R4 is -CH(Rs)(CH2)nR5, -C(CH3)2R6, -CH(R5)(CH2)nR5, -CH(R5)C6H4R6,
-CH(R5)C6H3(CO2H)2, CH(R5)C6H2(Cq2H)3, or an acid mimic;
RS is hydrogen, C]-C& a,lkyl, Ce-Cu aryl, aralkyl, Cj-Cg cycloalkyl, or
-(CH2)n(R7);
R is CO2H, tetrazole, or PO3H;
R7is
n is from 0 to 6;
p is from 0 to 3;
b is from 0 to 6; and
a is from 0 to 6.
•A. The compound of claim 1 wherein in the definition of RI, R2 and RS said Ct-Cu alkyl
unsubstituted d-C|2 alkyl or Ci-Qj perfiuoroalky! and said C|-Ce alkoxy is unsubstituted Cialkoxy
or Ci-Cs perfluoroalkoxy.
. 3 . The compound of claim 1, wherein:
RI is hydrogen, Ci-Ce alkyl or -(
4. The compound of claim 1 wherein R2 and Ra are independently hydrogen, unsubstituted
Ci-Cg alkyl, phenyl-(CH2)p-, halogen or Ct-Ca perfluoroalkyl.
5. The compound of any one of claims 1 to 4 wherein R4 is -CHRjCC^H,
-CHRSC6H4C02H, -CHR5C6H3{CO2H)2S -CH2-tetrazole or an acid mimic.
6. The compound of any one of claims 1 to 5 wherein R$ is hydrogen; unsubstituted phenyl;
unsubstituted benzyl; benzyl substituted with from 1 to 3 groups selected from the group
consisting of Ci-Cg alkyl, Ci-Ce alkoxy, hydroxy, Cs-Ce cycloalkyl, -(CH2)p-C3-Cc cycloalkyl,
halogen, Ci-Cj perfluoroalkyl, Ci-Cs perfluoroalkoxy, -(CH2)p-phenyl, and -0(CH2)p-phenyl; or
phenyl substituted with from I to 3 groups selected from CpCe alkyl, Ci-Cg alkoxy, hydroxy,
Q cycloalkyl, -(CHj)p-C3-C6 cycloalkyl, halogen, Ci:C3 perfluoroalkyl, Ci-Cs perfluoroalkoxy, -
(CH2)p-phenyI, and -O(CH2)p-phenyl.
7 . The compound of any one of claims 1 to 6 having Formula 2
Formula 2
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.
8 . The compound of any one of claims 1 to 7 having Formula 3:
Formula 3
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.
9 . The compound of any one of claims 1 to 8 having Formula 4:
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.
10 . The compound of any one of claims 1 to 9 wherein Ar is phenyl, naphthyl, furanyl,
thiophenyl, benzofuranyl, benzothiophenyl, indolyl, pyrazolyl, oxazolyl or fluorenyl.
1 1 . The compound of any one of claims 1 to 10 having Formula 5:
Formula 4
or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof wherein Rg,
Rio, RU and RIZ are independently hydrogen, Ci-Ce alkyl, C]-C6 alkoxy, hydroxy, C6.
e)alkyl, Cs-Cficycloalkyl, -(CH2)p-C3-C6cycloalkyl, halogen, -(CH2)P-phenyl, or -O(CH2)Pphenyl.
12. The compound of claim 11 wherein said Ci-Cg alkyl is unsubstituted Ci-Ce alkyl or Cr
Cj perfluoroalkyl; said Ci-Ce alkoxy is unsubstituted CpCs alkoxy or Ci-Cs perfluoroalkoxy.
13 . The compound of any one of claims 1 to 12 wherein R4 is -
'.4 . The compound of any one of claims 1 to 12 wherein R4 is -(CHy-tetrazole.
15 . The compound of any one of claims 1 to 12 wherein R4 is -
16 . The compound of claim 1 that is 3-phenyl-2-{[6-(5-phenyl-l//-pyrrol-2-yl)-2-
naphthyl]oxy}propanoicacid; 2-{[6-(l-benzyl-5-phenyl-17/-pyrrol-2-yl)-2-naphthyl]oxy}-3-
phenylpropanoic acid; {[6-(l-benzyl-5-phenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid; 2-
{[6-(lnethyl-5-phenyl-l#-pynxl-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid; 3-phenyl-2-
[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l^-pyrrol-2-yl}-2-naphthyl)oxy]propanoicacid; or
a pharmaceutically acceptable salt or ester form thereof.
17 . The compound of claim 1 that is [(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//'-pyrrol-
2-yl}-2-naphthyl)oxy]acetic acid; {[6-(l, 5 -diphenyl-l.#-pyrrol-2-yl)-2-naphthyl]oxy} acetic acid;
2-{[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid; 5-({[6-(5-phenyl-
I
l//-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-lH-tetraazole;5-({[6-(l-benzyl-5-phenyl-l//-pyirol-2-
yl)-2-naphthyl]oxy} methyl)- IH-tettaazole; or a pharmaceutically acceptable salt or ester form '
thereof.
I
1 8 . The compound of claim 1 that is 5-({[6-(l-methyl-5-phenyl-l#-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)-l//-tetraazole;
5-{[(6-{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthyl)oxy]methyl}-l-
tetraazole; S-Cfte-Cl.S-diphenyl-lH-pyrrol-yOnaphthylJoxyJmethyO-l/f-tetraazole-fe-
{5-phenyl-l-[4-(trifluoromethyl)benzyl]-l//-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoicacid;
4-({[6-(l,5-diphenyl-l//-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoic acid; or a
pharmaceutically acceptable salt or ester form thereof.
*
19. The compound of claim 1 that is 4-{[(6-{5rphenyl-l-[4-(trifluoromethyl)benzyl]-lfpyrrol-
2-yl}-2-naphthyl)oxy]methyl}isophthalicacid;4-({[6-(5-phenyl-l//'-pyrrol-2-yl)-2-
naphthyl]oxy}methyl)isophthalic acid; or a pharmaceutically acceptable salt or ester form
thereof.
20 . A. Jntf'tlW'dScftAilpiri'S'iiTgVUi'jSiilisfcring a compound of any one of claims 1 to 19 to a
subject.
21 . The method of claim 20 further comprising determining a level of PAI-1 activity in a
subject.
22 . The method of claim 21 wherein said determination is made before administration of
said compound.
23 . The method of claim 21 wherein said determination is made after administration of said
compound.
24 . A method of modulating PAI-1 activity comprising administering to a subject in need
thereof an effective amount of the compound of any one of claims 1 to 19.
25 . A method for treating impairment of the fibrinolytic system, thrombosis, atrial
fibrillation, pulmonary fibrosis, myocardial ischemia, stroke thromboernbolic complication of
surgery, cardiovascular disease, atherosclerotic plaque formation, chronic obstructive pulmonary
disease, renal fibrosis, polycystic ovary syndrome, diabetes, Alzheimer's disease, or cancer
comprising administering to a subject in need thereof a therapeutically effective amount of the
compound according to any one of claims 1 to 19.
26. The method of claims 24 or 25 wherein the effective amount is from about 25
mg/kg/day to about 200 mg/kg/day.
27 . The method of claim 25 wherein the thrombosis is selected from the group consisting of
venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein thrombosis.
28 . The method of claim 25 wherein the cardiovascular disease is caused by non-insulin
dependent diabetes mellitus in a subject.
* . • •
29 . A pharmaceutical composition comprising a compound of any one of claims 1 to 19, or a
pharmaceutically acceptable salt or ester form thereof, and a pharmaceutically acceptable
excipient or carrier.
30. d s i ' ? d h l c r d n g to any one of claims 1 to 19 in the manufacture of a
medicament for treating impairment of the fibrinolytic system, thrombosis, atrial fibrillation,
pulmonary fibrosis, thromboembolic complication of surgery, stroke, myocardial ischemia,
atherosclerotic plaque formation, cardiovascular disease, chronic obstructive pulmonary disease,
polycystic ovary syndrome, diabetes, Alzheimer's disease, cancer, or renal fibrosis.
31. The use according to claim 30 wherein the thrombosis is selected from the group
consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein
thrombosis.
32'. The use according to claim 30 wherein the cardiovascular disease is caused by noninsulin
dependent diabetes mellitus.
33. The Invention substantially such as herein before described.