U.S. patent application number 12/777956 was filed with the patent office on 2011-05-19 for factor xa inhibitors.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Zhaozhong JIA, Anjali PANDEY, Robert SCARBOROUGH, Yonghong SONG.
Application Number | 20110118244 12/777956 |
Document ID | / |
Family ID | 38480433 |
Filed Date | 2011-05-19 |
United States Patent
Application |
20110118244 |
Kind Code |
A2 |
SONG; Yonghong ; et
al. |
May 19, 2011 |
FACTOR XA INHIBITORS
Abstract
The present invention is directed to compounds of formula (I)
and pharmaceutically acceptable salts, esters, and prodrugs thereof
which are inhibitors of Factor Xa. The present invention is also
directed to intermediates used in making such compounds,
pharmaceutical compositions containing such a compound, methods to
prevent or treat a number of conditions characterized by undesired
thrombosis and methods of inhibiting the coagulation of a blood
sample.
Inventors: |
SONG; Yonghong; (Foster
City, CA) ; JIA; Zhaozhong; (San Mateo, CA) ;
SCARBOROUGH; Robert; (Half Moon Bay, CA) ; PANDEY;
Anjali; (Fremont, CA) |
Assignee: |
Millennium Pharmaceuticals,
Inc.
40 LANDSDOWNE STREET
CAMBRIDGE
MA
02139
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20100249117 A1 |
September 30, 2010 |
|
|
Family ID: |
38480433 |
Appl. No.: |
12/777956 |
Filed: |
May 11, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11/744735 |
Jul 27, 2010 |
7763608 |
|
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12777956 |
May 11, 2010 |
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60/883667 |
Jan 5, 2007 |
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60/797954 |
May 5, 2006 |
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Current U.S.
Class: |
514/227.8 ;
435/2; 514/230.8; 514/252.05; 514/255.05; 514/274; 514/318;
514/326; 514/333; 514/341; 514/392; 544/139; 544/238; 544/316;
544/408; 544/58.2; 546/194; 546/210; 546/256; 546/275.1;
548/312.4 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
29/00 20180101; A61P 35/00 20180101; A61P 43/00 20180101; A61P 9/00
20180101; C07D 401/14 20130101; A61P 7/00 20180101; A61P 11/00
20180101; C07D 409/14 20130101; A61P 9/10 20180101; A61P 11/06
20180101; C07D 413/14 20130101; C07D 417/14 20130101; A61P 19/02
20180101; A61P 9/04 20180101; A61P 1/04 20180101; A61P 25/00
20180101; A61P 37/06 20180101; A61P 7/04 20180101 |
Class at
Publication: |
514/227.8 ;
546/275.1; 514/341; 544/139; 514/230.8; 544/408; 514/255.05;
544/238; 514/252.05; 544/058.2; 544/316; 514/274; 548/312.4;
514/392; 546/210; 514/326; 546/194; 514/318; 546/256; 514/333;
435/002 |
International
Class: |
A61K 31/541 20060101
A61K031/541; C07D 401/14 20060101 C07D401/14; A61K 31/4439 20060101
A61K031/4439; C07D 413/14 20060101 C07D413/14; A61K 31/5377
20060101 A61K031/5377; C07D 241/18 20060101 C07D241/18; A61K 31/497
20060101 A61K031/497; C07D 403/14 20060101 C07D403/14; A61K 31/501
20060101 A61K031/501; C07D 279/12 20060101 C07D279/12; C07D 239/10
20060101 C07D239/10; A61K 31/513 20060101 A61K031/513; C07D 233/64
20060101 C07D233/64; A61K 31/4178 20060101 A61K031/4178; A61K
31/454 20060101 A61K031/454; A61K 31/4545 20060101 A61K031/4545;
A61K 31/444 20060101 A61K031/444; A61P 9/00 20060101 A61P009/00;
A01N 1/02 20060101 A01N001/02 |
Claims
1.-22. (canceled)
23. A compound of formula (II): ##STR112## wherein R.sup.1 is
selected from the group consisting of halogen, C.sub.1-8 alkyl,
C.sub.2-8 alkenyl and C.sub.2-8 alkynyl; R.sup.2 and R.sup.3 are
independently selected from the group consisting of hydrogen,
halogen, C.sub.1-4 alkyl, SR.sup.4a, S(O)R.sup.4a, and
S(O).sub.2R.sup.4a R.sup.4 is selected from the group consisting of
hydrogen, halogen, OR.sup.4a, SR.sup.4a, S(O)R.sup.4a,
S(O).sub.2R.sup.4aNR.sup.4aR.sup.4b, CO.sub.2R.sup.4a, ##STR113##
wherein each of these ring systems is optionally substituted with
from 1 to 3 substituents independently selected from the group
consisting of halogen, amino, oxo, C.sub.1-8 alkyl, C.sub.1-8
haloalkyl, hydroxy, C.sub.1-8 alkoxy, heterocycloalkyl, heteroaryl
and heteroaryl-C.sub.1-4 alkyl; each R.sup.4a or R.sup.4b is
independently hydrogen or C.sub.1-4 alkyl, optionally substituted
with from 1 to 2 substituents independently selected from the group
consisting of halogen, hydroxyl, alkoxy, heterocyclyl, oxo, amino
and carboxyl; R.sup.6 is selected from the group consisting of
hydrogen, halogen, and C.sub.1-4 alkyl; the subscript n is an
integer from 0 to 2; the wavy line indicates the point of
attachment to the rest of the molecule; or a pharmaceutically
acceptable ester or salt thereof.
24. The compound of claim 23, wherein R.sup.1 is C.sub.2-8
alkynyl.
25. The compound of claim 24, having the formula: ##STR114##
pharmaceutically acceptable ester or salt thereof.
26. The compound of claim 23, wherein R.sup.1 is halogen.
27. The compound of claim 23, having the formula selected from the
group consisting of ##STR115## ##STR116## ##STR117## ##STR118## or
a pharmaceutically acceptable ester or salt thereof.
28. The compound of claim 23, wherein R.sup.4 is hydrogen.
29. (canceled)
30. The compound of claim 23 that is in an isolated and purified
form.
31. A composition comprising a pharmaceutically acceptable
excipient and a compound of claim 23.
32. A method for preventing or treating thrombosis in a mammal
comprising of administering to said mammal a therapeutically
effective amount of a compound of claim 23.
33. The method in accordance with claim 32, wherein the condition
is selected from the group consisting of acute coronary syndrome,
myocardial infarction, unstable angina, refractory angina,
occlusive coronary thrombus occurring post-thrombolytic therapy or
post-coronary angioplasty, a thrombotically mediated
cerebrovascular syndrome, embolic stroke, thrombotic stroke,
transient ischemic attacks, venous thrombosis, deep venous
thrombosis, pulmonary embolus, coagulopathy, disseminated
intravascular coagulation, thrombotic thrombocytopenic purpura,
thromboangiitis obliterans, thrombotic disease associated with
heparin-induced thrombocytopenia, thrombotic complications
associated with extracorporeal circulation, thrombotic
complications associated with instrumentation such as cardiac or
other intravascular catheterization, intra-aortic balloon pump,
coronary stent or cardiac valve, and conditions requiring the
fitting of prosthetic devices.
34. A method for inhibiting coagulation of a blood sample
comprising contacting said sample with a compound of claim 23.
35. The method of claim 33, wherein the condition is selected from
the group consisting of embolic stroke, thrombotic stroke, venous
thrombosis, deep venous thrombosis, acute coronary syndrome, and
myocardial infarction.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a Continuation Patent Application of
U.S. Utility patent application Ser. No. 11/744,735 filed May 4,
2007, which claims the benefit under 35 U.S.C. .sctn.119 (e) of
U.S. Provisional Application No. 60/883,667, filed Jan. 5, 2007,
and U.S. Provisional Application No. 60,797,954, filed May 5, 2006,
both of which are hereby incorporated by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention is directed to substituted imidazole
compounds which act as inhibitors of Factor Xa. This invention is
also directed to pharmaceutical compositions containing the
substituted imidazole compounds and methods of using the compounds
or compositions to treat a condition characterized by undesired
thrombosis. The invention is also directed to methods of making the
compounds described herein.
[0004] 2. State of the Art
[0005] Hemostasis, the control of bleeding, occurs by surgical
means, or by the physiological properties of vasoconstriction and
coagulation. This invention is particularly concerned with blood
coagulation and ways in which it assists in maintaining the
integrity of mammalian circulation after injury, inflammation,
disease, congenital defect, dysfunction or other disruption.
Although platelets and blood coagulation are both involved in
restoring hemostasis and in thrombotic diseases, certain components
of the coagulation cascade are primarily responsible for the
amplification and acceleration of the processes involved in
platelet aggregation and fibrin deposition which are major events
in thrombosis and hemostasis.
[0006] Clot formation involves the conversion of fibrinogen to
fibrin which polymerizes into a network to restore hemostasis after
injury. A similar process results in occluded blood vessels in
thrombotic diseases. The conversion of fibrinogen to fibrin is
catalyzed by thrombin, the end product of a series of reactions in
the blood coagulation cascade. Thrombin is also a key player in
activating platelets, thereby contributing to thrombosis under
conditions of both arterial and venous blood flow. For these
reasons, it has been postulated that efficient regulation of
thrombin can lead to efficient regulation of thrombosis. Several
classes of currently used anticoagulants directly or indirectly
affect thrombin (i.e. unfractionated heparins, low-molecular weight
heparins, heparin-like compounds, pentasaccharide and warfarin).
Direct or indirect inhibition of thrombin activity has also been
the focus of a variety of anticoagulants in clinical development
(reviewed by Eriksson and Quinlan, Drugs 11: 1411-1429, 2006).
[0007] Prothrombin, the precursor for thrombin, is converted to the
active enzyme by factor Xa. Localized activation of tissue
factor/factor VIIa mediated factor Xa generation is amplified by
the factor IXa/factor VIIIa complex and leads to prothrombinase
assembly on activated platelets. Factor Xa, as a part of the
prothrombinase complex, is the sole enzyme responsible for
sustained thrombin formation in the vasculature. Factor Xa is a
serine protease, the activated form of its precursor Factor X, and
a member of the calcium ion binding, gamma carboxyglutamic acid
(GLA)-containing, vitamin K dependent, blood coagulation factors.
Unlike thrombin, which acts on a variety of protein substrates
including fibrinogen and the PAR receptors (Protease activated
receptors, Coughlin, J Thrombosis Haemostasis 3: 1800-1814, 2005),
factor Xa appears to have a single physiologic substrate, namely
prothrombin. Since one molecule of factor Xa may be able to
generate greater than 1000 molecules of thrombin (Mann, et al., J.
Thrombosis. Haemostasis 1: 1504-1514, 2003), direct inhibition of
factor Xa as a way of indirectly inhibiting the formation of
thrombin may be an efficient anticoagulant strategy. This assertion
is based on the key role of prothrombinase in thrombin synthesis
and on the fact that inhibition of prothrombinase will have a
pronounced effect on the overall platelet aggregation and clotting
pathways.
[0008] Activated proteases such as factor VIIa, factor IXa or
factor Xa have poor proteolytic activity on their own. However,
their assembly into cofactor-dependent, membrane-bound complexes
significantly enhances their catalytic efficiencies. This effect is
most dramatic for factor Xa, where the efficiency is increased by a
factor of 105 (Mann, et al., Blood 76(1):1-16, 1990). Due to the
higher concentration of the zymogens present in blood (1.4
micromolar prothrombin versus 150 nanomolar factor X) and the
kinetics of activation, a smaller amount of factor Xa than thrombin
needs to be inhibited to achieve an anticoagulant effect. Indirect
proof of the hypothesis of superiority of factor Xa as a
therapeutic target compared to thrombin can also be found in
clinical trials for the prevention of deep vein thrombosis.
Fondaparinux, an antithrombin III dependent factor Xa inhibitor,
was proven to be superior to enoxaparin (a low molecular weight
heparin that inhibits both thrombin and factor Xa) in four trials
of orthopedic surgery (Turpie, et al., Archives Internal Medicine
162(16): 1833-1840, 2002). Therefore, it has been suggested that
compounds which selectively inhibit factor Xa may be useful as in
vitro diagnostic agents, or for therapeutic administration in
certain thrombotic disorders, see e.g., WO 94/13693.
[0009] Several Factor Xa inhibitors have been reported as
polypeptides derived from hematophagous organisms, as well as
compounds which are not large polypeptide-type inhibitors.
Additional Factor Xa inhibitors include small molecule organic
compounds, such as nitrogen containing heterocyclic compounds which
have amidino substituent groups, wherein two functional groups of
the compounds can bind to Factor Xa at two of its active sites. For
example, WO 98/28269 describes pyrazole compounds having a terminal
C(.dbd.NH)--NH.sub.2 group; WO 97/21437 describes benzimidazole
compounds substituted by a basic radical which are connected to a
naphthyl group via a straight or branched chain alkylene,
--C(.dbd.O) or --S(.dbd.O).sub.2 bridging group; WO 99/10316
describes compounds having a 4-phenyl-N-alkylamidino-piperidine and
4-phenoxy-N-alkylamidino-piperidine group connected to a
3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP
798295 describes compounds having a
4-phenoxy-N-alkylamidino-piperidine group connected to an
amidinonaphthyl group via a substituted or unsubstituted
sulfonamide or carboxamide bridging group.
[0010] There exists a need for effective therapeutic agents for the
regulation of hemostasis, and for the prevention and treatment of
thrombus formation and other pathological processes in the
vasculature induced by thrombin such as restenosis and
inflammation. In particular, there continues to be a need for
compounds which selectively inhibit factor Xa or its precursors.
Compounds that have different combinations of bridging groups and
functional groups than compounds previously discovered are needed,
particularly compounds which selectively or preferentially bind to
Factor Xa. Compounds with a higher degree of binding to Factor Xa
than to thrombin are desired, especially those compounds having
good bioavailability and/or solubility.
BRIEF SUMMARY OF THE INVENTION
[0011] In one aspect, the present invention provides compounds
having the following formula: ##STR1##
[0012] In formula (I), the symbol Z is selected from the group
consisting of: ##STR2##
[0013] The symbol R.sup.1 is selected from the group consisting of
halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl.
The symbol R.sup.1a is hydrogen or C.sub.1-4 alkyl.
[0014] The symbol R.sup.2 and R.sup.3 are independently selected
from the group consisting of hydrogen, halogen, C.sub.1-4alkyl,
SR.sup.4a, S(O)R.sup.4aS(O).sub.2R.sup.4a,
COR.sup.4aCO.sub.2R.sup.4a, CONR.sup.4aR.sup.4b CN, and
S(O).sub.2NR.sup.4aR.sup.4b.
[0015] The symbol R.sup.4 represents a moiety independently
selected from the group consisting of hydrogen, halogen, OR.sup.4a,
SR.sup.4aS(O)R.sup.4a, S(O).sub.2R.sup.4aNR.sup.4aR.sup.4bC.sub.2R
##STR3## wherein each of these ring systems is optionally
substituted with from 1 to 3 substituents independently selected
from the group consisting of halogen, amino, oxo, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, hydroxy, C.sub.1-8 alkoxy, heterocycloalkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl.
[0016] The symbols R.sup.4a or R.sup.4b are independently hydrogen
or C.sub.1-4alkyl, optionally substituted with from 1 to 2
substituents independently selected from the group consisting of
halogen, hydroxyl, alkoxy, heterocyclyl, oxo, amino, and carboxyl.
The subscript n is an integer from 0 to 2.
[0017] The symbol R.sup.5 is selected from the group consisting of:
##STR4## ##STR5## wherein each of these ring systems is optionally
substituted with from 1 to 3 substituents independently selected
from the group consisting of halogen, C.sub.1-8 alkyl, C.sub.1-8
haloalkyl, --NH--C(O)--C.sub.1-8alkyl, hydroxy, amino, oxo,
C.sub.1-8alkoxy, heterocycloalkyl, heteroaryl, and
heteroaryl-C.sub.1-4 alkyl, with the proviso that when R.sup.5 is
##STR6## then there cannot be an alkyl (or substituted alkyl)
substituent in the 5-position of the R.sup.5 ring.
[0018] Surprisingly, it has been found that the inclusion of the
R.sup.5 ring group having at least one exo bond (i.e., .dbd.O,
.dbd.N--R, .dbd.S) and being attached through the nitrogen atom
provides improved pharmacokinetic properties.
[0019] The symbol R.sup.6 is selected from the group consisting of
hydrogen, halogen, and C.sub.1-4 alkyl.
[0020] The symbol R.sup.7 is selected from the group consisting of
hydrogen, C.sub.1-4 alkyl, cyano, optionally substituted phenyl,
and C(O)R.sup.9 wherein R.sup.9 is C.sub.1-4 alkyl or amino.
[0021] The symbol R.sup.8 is selected from the group consisting of
hydrogen and C.sub.1-4 alkyl.
[0022] The wavy line indicates the point of attachment to the rest
of the molecule.
[0023] The present invention also contemplates pharmaceutically
acceptable salts, esters, and prodrugs of the compounds of formula
I.
[0024] The present invention further provides compounds in purified
forms, chemical intermediates, pharmaceutical compositions and
methods for preventing or treating a condition in a mammal
characterized by undesired thrombosis comprising the step of
administering to the mammal a therapeutically effective amount of a
compound of the present invention. Such conditions include but are
not limited to acute coronary syndrome, myocardial infarction,
unstable angina, refractory angina, occlusive coronary thrombus
occurring post-thrombolytic therapy or post-coronary angioplasty, a
thrombotically mediated cerebrovascular syndrome, embolic stroke,
thrombotic stroke, transient ischemic attacks, venous thrombosis,
deep venous thrombosis, pulmonary embolus, coagulopathy,
disseminated intravascular coagulation, thrombotic thrombocytopenic
purpura, thromboangiitis obliterans, thrombotic disease associated
with heparin-induced thrombocytopenia, thrombotic complications
associated with extracorporeal circulation, thrombotic
complications associated with instrumentation such as cardiac or
other intravascular catheterization, intra-aortic balloon pump,
coronary stent or cardiac valve, conditions requiring the fitting
of prosthetic devices, and the like.
[0025] The present invention further provides methods for
inhibiting the coagulation of a blood sample comprising contacting
the sample with a compound of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1. Shows mean plasma concentration-time profiles of
compound 10 in male Sprague-Dawley rats after 1 mg/kg intravenous
(.circle-solid.) and 10 mg/kg oral (.box-solid.) administration
(n=3/group). Plasma samples were measured using LC/MS/MS.
[0027] FIG. 2. Mean plasma concentration-time profiles of compound
10 in male beagle dogs after 1 mg/kg intravenous (.circle-solid.)
and 5 mg/kg oral (.box-solid.) administration (n=3/group). Plasma
samples were measured using LC/MS/MS.
[0028] FIG. 3. Shows mean plasma concentration-time profiles of
compound 10 in male rhesus monkeys after 1 mg/kg intravenous
(.circle-solid.) and 5 mg/kg oral (.box-solid.) administration
(n=3/group). Plasma samples were measured using LC/MS/MS.
DETAILED DESCRIPTION OF THE INVENTION
1. Abbreviations and Definitions
[0029] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain hydrocarbon radical, having the number of carbon atoms
designated (i.e. C.sub.1-8 means one to eight carbons). Examples of
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
and the like. The term "alkenyl" refers to an unsaturated alkyl
group is one having one or more, preferably 1 to 3, double bonds.
Similarly, the term "alkynyl" refers to an unsaturated alkyl group
having one or more, preferably 1 to 3, triple bonds. Examples of
such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,
2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,
3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the
higher homologs and isomers.
[0030] The term "cycloalkyl" refers to hydrocarbon rings having the
indicated number of ring atoms (e.g., C.sub.3-6 cycloalkyl) and
being fully saturated between ring vertices. The term
"cycloalkenyl" refers to a cycloalkyl group that has at least one
point of alkenyl unsaturation between the ring vertices. The term
"cycloalkynyl" refers to a cycloalkyl group that has at least one
point of alkynyl unsaturation between the ring vertices. When
"cycloalkyl" is used in combination with "alkyl," as in C.sub.3-5
cycloalkyl-alkyl, the cycloalkyl portion is meant to have the
stated number of carbon atoms (e.g., from three to five carbon
atoms), while the alkyl portion is an alkylene moiety having from
one to three carbon atoms (e.g., --CH.sub.2--, --CH.sub.2CH.sub.2--
or --CH.sub.2CH.sub.2CH.sub.2--).
[0031] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified by --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an
alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with
those groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having four or fewer
carbon atoms.
[0032] Unless stated otherwise, alkyl, alkoxy, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylene refer to both
substituted and unsubstituted groups in which 1 or more, such as 1
to 5, hydrogen atoms is replaced by a substituent independently
selected from the group consisting of .dbd.O, .dbd.S, acyl
(--C(O)--R), acyloxy (--O--C(O)--R), alkoxy, alkoxyamino
(--NH--O-alkyl), hydroxyamino (--NH--OH), amino, substituted amino
such as --NH.sub.2 where one or more of the hydrogens may be
optionally replaced by another suitable group, such as alkylamino
and dialkylamino, or wherein the amino group may be a cyclic amine,
aryl, heterocyclyl, azido (--N.sub.3), carboxyl (--C(O)OH),
alkoxycarbonyl (--C(O)--O-alkyl), amido (--C(O)-amino), cyano
(--CN), cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro,
sulfonylamino (--N(R)--S(O).sub.2--OR), aminosulfonyl
(--S(O).sub.2-amino), sulfanyl (--S--R), sulfinyl (--S(O)--R),
sulfonyl (--S(O).sub.2--R), and sulfonic acid (--S(O).sub.2--OH),
wherein each R may independently be hydrogen, alkyl, cycloalkyl,
aryl, heteroaryl, and heterocycle.
[0033] The terms "alkoxy," "alkylamino," and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom (--O-alkyl), an amino group, or a sulfur atom
(--S-alkyl), respectively. Additionally, for dialkylamino groups
(typically provided as --NR.sup.aR.sup.b or a variant thereof,
where R.sup.a and R.sup.b are independently alkyl or substituted
alkyl), the alkyl portions can be the same or different and can
also be combined to form a 3-7 membered ring with the nitrogen atom
to which each is attached. Accordingly, a group represented as
--NR.sup.aR.sup.b is meant to include a cyclic aminie having 3 to 6
carbon atoms and optionally additional heteroatoms, such as O, S,
and N, including but not limited to piperidinyl, pyrrolidinyl,
morpholinyl, azetidinyl and the like.
[0034] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl
up to the maximum number of halogens permitted. For example, the
term "C.sub.1-8 haloalkyl" is meant to include trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0035] The term "hydroxy" or "hydroxyl" refers to the group
--OH.
[0036] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, hydrocarbon group containing from 6 to
14 carbon atoms, which can be a single ring or multiple rings (up
to three rings) which are fused together or linked covalently. The
term "heteroaryl" refers to aryl groups (or rings) that contain
from one to five heteroatoms selected from N, O, and S, wherein the
nitrogen and sulfur atoms are optionally oxidized, and the nitrogen
atom(s) are optionally quaternized. A heteroaryl group can be
attached to the remainder of the molecule through a heteroatom or
through a carbon atom and can contain 5 to 10 carbon atoms.
Non-limiting examples of aryl groups include phenyl, naphthyl and
biphenyl, while non-limiting examples of heteroaryl groups include
1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,
2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,
5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,
5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl,
5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl,
5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. If not specifically
stated, substituents for each of the above noted aryl and
heteroaryl ring systems are selected from the group of acceptable
substituents described below.
[0037] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" is meant to include those radicals in which an aryl
group is attached to an alkyl group (e.g., benzyl, phenethyl,
pyridylmethyl and the like).
[0038] The term "heterocycle" or "heterocyclyl" or "hetreocyclic"
refers to a saturated or unsaturated non-aromatic cyclic group
containing at least one sulfur, nitrogen or oxygen heteroatom. Each
heterocycle can be attached at any available ring carbon or
heteroatom. Each heterocycle may have one or more rings. When
multiple rings are present, they can be fused together or linked
covalently. Each heterocycle must contain at least one heteroatom
(typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or
sulfur. Preferably, these groups contain 1-10 carbon atoms, 0-5
nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More
preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur
atoms and 0-1 oxygen atoms.
[0039] Non-limiting examples of heterocycle and heteroaryl groups
include pyridine, pyridimidine, pyrazine, morpholin-3-one,
piperazine-2-one, pyridine-2-one, piperidine, morpholine,
piperazine, isoxazole, isothiazole, pyrazole, imidazole, oxazole,
thiazole, isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole,
1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,
1,2,4-oxadiazole, 1,2,4-thiadiazole, pyrazol-5-one,
pyrrolidine-2,5-dione, imidazolidine-2,4-dione, pyrrolidine,
pyrrole, furan, thiophene, and the like.
[0040] The term "heterocycloalkyl" refers to the group
alkylene-heterocycle, wherein both heterocycle and alkylene are as
defined above.
[0041] The above terms (e.g., "aryl" and "heteroaryl"), in some
embodiments, will include both substituted and unsubstituted forms
of the indicated radical. Preferred substituents for each type of
radical are provided below. For brevity, the terms aryl and
heteroaryl will refer to substituted or unsubstituted versions as
provided below.
[0042] Substituents for the aryl, heteroaryl, and heterocycle
groups are varied and are generally selected from: -halogen, --OR',
--OC(O)R', --NR'R'', --SR, --R', --CN, --NO.sub.2, --CO.sub.2R',
--CONR'R'', --C(O)R', --OC(O)NR'R'', --NR''C(O)R',
--NR''C(O).sub.2R', --NR'--C(O)NR''R''', --NH--C(NH.sub.2).dbd.NH,
--NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NR'S(O).sub.2R'', --N.sub.3,
perfluoro(C.sub.1-C.sub.4)alkoxy, and
perfluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to
the total number of open valences on the ring system; and where R',
R'' and R''' are independently selected from hydrogen, C.sub.1-8
alkyl, C.sub.3-6 cycloalkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
unsubstituted aryl and heteroaryl, (unsubstituted
aryl)-C.sub.1-4alkyl, and unsubstituted aryloxy-C.sub.1-4 alkyl.
Other suitable substituents include each of the above aryl
substituents attached to a ring atom by an alkylene tether of from
1-4 carbon atoms. This group of substituents is also used to
describe the substituents for optionally substituted phenyl.
[0043] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CH.sub.2).sub.q-U-, wherein T and U are
independently --NH--, --O--, --CH.sub.2-- or a single bond, and q
is an integer of from 0 to 2. Alternatively, two of the
substituents on adjacent atoms of the aryl or heteroaryl ring may
optionally be replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B--, wherein A and B are independently
--CH.sub.2--, --O--, --NH--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 3. One of the single bonds of the new ring so formed may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CH.sub.2).sub.s--X--(CH.sub.2).sub.t--, where s and t are
independently integers of from 0 to 3, and X is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituent R' in --NR'-- and --S(O).sub.2NR'-- is selected from
hydrogen or unsubstituted C.sub.1-6 alkyl.
[0044] "Amino" refers to the group --NH.sub.2 and unless otherwise
specificied, also refers to "substituted amino."
[0045] "Substituted amino" refers to the group --NR'R'' where R'
and R'' are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl,
heteroaryl, heterocyclic, --SO.sub.2-alkyl, --SO.sub.2-alkenyl,
--SO.sub.2-cycloalkyl, --SO.sub.2-cycloalkenyl, --SO.sub.2-aryl,
--SO.sub.2-heteroaryl, and --SO.sub.2-heterocyclic, and wherein R'
and R'' are optionally joined, together with the nitrogen bound
thereto to form a heterocyclic or substituted heterocyclic group,
provided that R' and R'' are both not hydrogen, and wherein alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and
heterocyclic are as defined herein. When R' is hydrogen and R'' is
alkyl, the substituted amino group is sometimes referred to herein
as alkylamino. When R' and R'' are alkyl, the substituted amino
group is sometimes referred to herein as dialkylamino. When
referring to a monosubstituted amino, it is meant that either R' or
R'' is hydrogen but not both. When referring to a disubstituted
amino, it is meant that neither R' nor R'' are hydrogen.
[0046] "Carbonyl" refers to the divalent group --C(O)-- which is
equivalent to --C(.dbd.O)--.
[0047] "Cyano" refers to the group --CN.
[0048] "Oxo" refers to the atom (.dbd.O) or (--O.sup.-).
[0049] As used herein, the term "heteroatom" is meant to include
oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
[0050] The term "pharmaceutically acceptable salts" is meant to
include salts of the active compounds which are prepared with
relatively nontoxic acids or bases, depending on the particular
substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of salts derived from pharmaceutically-acceptable inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable
organic bases include salts of primary, secondary and tertiary
amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, malonic, benzoic, succinic,
suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, e.g., Berge, S. M., et al, "Pharmaceutical
Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain
specific compounds of the present invention contain both basic and
acidic functionalities that allow the compounds to be converted
into either base or acid addition salts.
[0051] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0052] In addition to salt forms, the present invention provides
compounds which are in a ester form. For example, in the case of a
carboxylic acid (--COOH) or alcohol group being present in the
compounds of the present invention, pharmaceutically acceptable
esters of carboxylic acid derivatives, such as methyl, ethyl, or
pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetate
or maleate, can be employed. The invention includes those esters
and acyl groups known in the art for modifying the solubility or
hydrolysis characteristics for use as sustained-release or prodrug
formulations.
[0053] In addition to salt forms, the present invention provides
compounds which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0054] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are intended to be encompassed within the scope of the
present invention. Certain compounds of the present invention may
exist in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated by the
present invention and are intended to be within the scope of the
present invention.
[0055] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers, regioisomers and
individual isomers (e.g., separate enantiomers) are all intended to
be encompassed within the scope of the present invention. The
compounds of the present invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present invention,
whether radioactive or not, are intended to be encompassed within
the scope of the present invention.
2. Embodiments of the Invention
[0056] a. Compounds
[0057] In one aspect, the present invention provides compounds
having the following formula: ##STR7##
[0058] In formula (I), the symbol Z is selected from the group
consisting of: ##STR8##
[0059] The symbol R.sup.1 is selected from the group consisting of
halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl.
The symbol R.sup.1a is hydrogen or C.sub.1-4 alkyl.
[0060] The symbol R.sup.2 and R.sup.3 are independently selected
from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl,
SR.sup.4a, S(O)R.sup.4a, S(O).sub.2R.sup.4a, COR.sup.4a,
CO.sub.2R.sup.4a, CONR.sup.4aR.sup.4b CN, and
S(O).sub.2NR.sup.4aR.sup.4b.
[0061] The symbol R.sup.4 represents a moiety independently
selected from the group consisting of hydrogen, halogen, OR.sup.4,
SR.sup.4,
S(O)R.sup.4aS(O).sub.2R.sup.4aNR.sup.4aR.sup.4bCO.sub.2R.sup.4a,
##STR9## wherein each of these ring systems is optionally
substituted with from 1 to 3 substituents independently selected
from the group consisting of halogen, amino, oxo, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, hydroxy, C.sub.1-8 alkoxy, heterocycloalkyl,
heteroaryl, and heteroaryl-C.sub.1-4 alkyl.
[0062] The symbols R.sup.4a or R.sup.4b are independently hydrogen
or C.sub.1-4 alkyl, optionally substituted with from 1 to 2
substituents independently selected from the group consisting of
halogen, hydroxyl, alkoxy, heterocyclyl, oxo, amino, and
carboxyl.
[0063] The subscript n is an integer from 0 to 2.
[0064] The symbol R.sup.5 is selected from the group consisting of:
##STR10## ##STR11## wherein each of these ring systems is
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halogen, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, --NH--C(O)--C.sub.1-8 alkyl, hydroxy, amino,
oxo, C.sub.1-8 alkoxy, heterocycloalkyl, heteroaryl, and
heteroaryl-C.sub.1-4 alkyl, with the proviso that when R.sup.5 is
##STR12## then there cannot be an alkyl (or substituted alkyl)
substituent in the 5-position of the R.sup.5 ring.
[0065] The structure shown above as: ##STR13## includes both the
cis and trans isomers, i.e., ##STR14##
[0066] The symbol R.sup.6 is selected from the group consisting of
hydrogen, halogen, and C.sub.1-4 alkyl.
[0067] The symbol R.sup.7 is selected from the group consisting of
hydrogen, C.sub.1-4 alkyl, cyano, optionally substituted phenyl,
and C(O)R.sup.9 wherein R.sup.9 is C.sub.1-4 alkyl or amino.
[0068] The symbol R.sup.8 is selected from the group consisting of
hydrogen and C.sub.1-4 alkyl.
[0069] The wavy line indicates the point of attachment to the rest
of the molecule.
[0070] The present invention also contemplates pharmaceutically
acceptable salts, esters, and prodrugs of the compounds of formula
(I).
[0071] With the above formula, are a number of specific embodiments
of the invention. In one group of embodiments, R.sup.2, R.sup.3 and
R.sup.6 are hydrogen. In one group of embodiments, R.sup.2 is
selected from the group consisting of hydrogen, C.sub.1-4 alkyl,
SR.sup.4a, S(O)R.sup.4a, S(O).sub.2R.sup.4a, COR.sup.4a,
CO.sub.2R.sup.4a, CONR.sup.4aR.sup.4b, CN, and
S(O).sub.2NR.sup.4aR.sup.4b. In one group of embodiments, R.sup.2
is selected from the group consisting of hydrogen, methyl,
--S-methyl, --S(O)-methyl, and --S(O).sub.2-methyl. In one group of
embodiments, R.sup.3 is hydrogen or methyl. In one group of
embodiments, R.sup.6 is hydrogen or fluoro. In one group of
embodiments, R.sup.4 is selected from the group consisting of
hydrogen, halogen, OR.sup.4a, S(O)R.sup.4a, S(O).sub.2R.sup.4a,
NR.sup.4aR.sup.4b, CO.sub.2R.sup.4a, ##STR15## wherein each of
these ring systems is optionally substituted with from 1 to 3
substituents independently selected from the group consisting of
halogen, amino, oxo, C.sub.1-8alkyl, C.sub.1-8 haloalkyl, hydroxy,
C.sub.1-8alkoxy, heterocycloalkyl, heteroaryl, and
heteroaryl-C.sub.1-4 alkyl; and each R.sup.4a or R.sup.4b is
independently hydrogen or C.sub.1-4 alkyl, optionally substituted
with hydroxyl, alkoxy, or heterocyclyl, and the wavy line indicates
the point of attachment to the rest of the molecule. The
superscript n is 0, 1, and 2.
[0072] In one embodiment, R.sup.4 is selected from the group
consisting of hydrogen, hydroxyl, fluoro, S(O)CH.sub.3,
S(O).sub.2CH.sub.3, NH(CH.sub.2).sub.2OH, --C(O).sub.2CH.sub.3,
--O(CH.sub.2).sub.2OCH.sub.3, --OCH.sub.2CH(OH)CH.sub.2OH,
##STR16##
[0073] In another group of embodiments, R.sup.5 is ##STR17##
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halogen, amino,
C.sub.1-8alkyl, C.sub.1-8 haloalkyl, hydroxy, C.sub.1-8alkoxy,
heterocycloalkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl.
[0074] In another embodiment, the invention contemplates a compound
having the formula: ##STR18## and pharmaceutically acceptable
salts, esters and prodrugs thereof.
[0075] In another group of embodiments, R.sup.5 is ##STR19##
optionally substituted with from 1 to 3 substituents independently
selected from the group consisting of halogen, amino,
C.sub.1-8alkyl, C.sub.1-8 haloalkyl, hydroxy, C.sub.1-8 alkoxy,
heterocycloalkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl; and
the subscript n is 0, 1, or 2.
[0076] In another embodiment, the invention contemplates compounds
having the formulas: ##STR20## and pharmaceutically acceptable
salts, esters and prodrugs thereof.
[0077] In another group of embodiments, R.sup.5 is selected from
the group consisting of ##STR21## wherein each of these ring
systems is optionally substituted with from 1 to 3 substituents
independently selected from the group consisting of halogen,
C.sub.1-8 alkyl, --NH--C(O)--C.sub.1-8 alkyl, C.sub.1-8 haloalkyl,
hydroxy, amino, oxo, C.sub.1-8 alkoxy, heterocycloalkyl, heteroaryl
and heteroaryl-C.sub.1-4 alkyl and R.sup.8 is hydrogen or C.sub.1-4
alkyl.
[0078] In another embodiment, the invention contemplates compounds
having the formula selected from the group consisting of: ##STR22##
##STR23## ##STR24## ##STR25## and pharmaceutically acceptable
salts, esters and prodrugs thereof.
[0079] In one group of embodiments, R.sup.5 is ##STR26## wherein
R.sup.7 is selected from the group consisting of hydrogen,
C.sub.1-4 alkyl, cyano, optionally substituted phenyl, and
C(O)R.sup.9. R.sup.9 is C.sub.1-4 alkyl or amino.
[0080] In those embodiments, the invention includes compounds
selected from: ##STR27## and pharmaceutically acceptable salts,
esters and prodrugs thereof.
[0081] In one group of embodiments, Z is selected from the group
consisting of: ##STR28## and R.sup.1 is halogen or C.sub.2-8
alkynyl and R.sup.1a is hydrogen or methyl.
[0082] In another group of embodiments, Z is: ##STR29##
[0083] In another embodiment, the invention contemplates compounds
having the formula: ##STR30## and pharmaceutically acceptable
salts, esters and prodrugs thereof.
[0084] In another group of embodiments, Z is: ##STR31## and R.sup.1
is halogen or C.sub.2-8 alkynyl.
[0085] In another group of embodiments, Z is: ##STR32## where
R.sup.1 is halogen or C.sub.2-8 alkynyl and R.sup.1a is hydrogen or
methyl.
[0086] The invention contemplates compounds having the formula:
##STR33## and pharmaceutically acceptable salts, esters and
prodrugs thereof.
[0087] In another group of embodiments, the compound has the
following formula: ##STR34##
[0088] With reference to formula (II), R.sup.1 is selected from the
group consisting of halogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, and
C.sub.2-8alkynyl; R.sup.2 and R.sup.3 are independently selected
from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl,
SR.sup.4a, S(O)R.sup.4a, and S(O).sub.2R.sup.4a; and R.sup.4 is
selected from the group consisting of hydrogen, halogen, OR.sup.4a,
SR.sup.4a, S(O)R.sup.4aS(O).sub.2R.sup.4aNR.sup.4aR.sup.4b,
CO.sub.2R.sup.4a, ##STR35## [0089] wherein each of these ring
systems is optionally substituted with from 1 to 3 substituents
independently selected from the group consisting of halogen, amino,
oxo, C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, hydroxy, C.sub.1-8
alkoxy, heterocycloalkyl, heteroaryl, and heteroaryl-C.sub.1-4
alkyl; [0090] each R.sup.4a or R.sup.4b is independently hydrogen
or C.sub.1-4 alkyl, optionally substituted with from 1 to 2
substituents independently selected from the group consisting of
halogen, hydroxyl, alkoxy, heterocyclyl, oxo, amino and carboxyl;
[0091] R.sup.6 is selected from the group consisting of hydrogen,
halogen, and C.sub.1-4 alkyl; [0092] the subscript n is an integer
from 0 to 2; [0093] the wavy line indicates the point of attachment
to the rest of the molecule; [0094] and pharmaceutically acceptable
salts, esters and prodrugs thereof.
[0095] In another group of embodiments, the R.sup.1 is C.sub.2-8
alkynyl.
[0096] In another embodiment, the compound has the formula:
##STR36## and the invention contemplates pharmaceutically
acceptable salts, esters and prodrugs thereof.
[0097] In another group of embodiments, R.sup.1 is halogen.
[0098] In another embodiment, the compound is selected from the
group consisting of: ##STR37## ##STR38## ##STR39## ##STR40## and
pharmaceutically acceptable salts, esters and prodrugs thereof.
[0099] In another group of embodiments, R.sup.4 is hydrogen.
##STR41## and pharmaceutically acceptable salts, esters and
prodrugs thereof.
[0100] In another group of embodiments, the compound of the
invention is in an isolated and purified form.
[0101] Within the present invention, the compounds provided in the
examples below are each preferred embodiments, along with their
pharmaceutically acceptable salts, esters and prodrugs thereof.
Preferred examples of compounds of formula (I) include: [0102]
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-
thiophene-2-carboxamide; [0103]
5-Chloro-N-((1-(4-(3-oxomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thioph-
ene-2-carboxamide; [0104]
5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-
thiophene-2-carboxamide; [0105]
5-Chloro-N-((1-(4-(6-oxopyridazin-1(6H)-yl)phenyl)-1H-imidazol-4-yl)methy-
l)thiophene-2-carboxamide; [0106]
5-Chloro-N-((1-(4-(2-oxo-6-methylpyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0107]
5-Chloro-N-((1-(4-(3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)th-
iophene-2-carboxamide; [0108]
5-Chloro-N-((1-(4-(1,1-dioxo-3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide; [0109]
5-Chloro-N-((1-(4-(1,3-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methy-
l)thiophene-2-carboxamide; [0110]
5-Chloro-N-((1-(4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol-
-4-yl)methyl)thiophene-2-carboxamide; [0111]
5-Chloro-N-((1-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl-
)thiophene-2-carboxamide; [0112]
5-Chloro-N-((1-(4-(2,5-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4-yl)methy-
l)thiophene-2-carboxamide; [0113]
5-Chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0114]
5-Chloro-N-((1-(2-(methylsulfonyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide; [0115]
5-chloro-N-((1-(2-(methylsulfinyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide; [0116]
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-thiomorpholinophenyl)-1H-imid-
azol-4-yl)methyl)thiophene-2-carboxamide; [0117]
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(1,1-dioxo-thiomorpholin-4-yl-
)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0118]
5-Chloro-N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)--
1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0119]
5-Chloro-N-((1-(2-(2-hydroxyethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)--
1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0120]
5-Chloro-N-((1-(2-hydroxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; [0121]
5-Chloro-N-((1-(2-methoxycarbonyl-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imi-
dazol-4-yl)methyl)thiophene-2-carboxamide; [0122]
5-Chloro-N-((1-(4-(2-thioxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)meth-
yl)thiophene-2-carboxamide; [0123]
N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indol-
e-6-carboxamide; [0124]
5-Ethynyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl-
)thiophene-2-carboxamide; [0125]
5-Chloro-N-((1-(4-(2-(cyanoimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0126]
5-Chloro-N-((1-(4-(2-(methylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; [0127]
5-Chloro-N-((1-(4-(2-(4-methoxyphenylimino)pyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide; [0128]
N-((1-(4-(2-(acetylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl-
)-5-chlorothiophene-2-carboxamide; [0129]
4-Chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)-1H-pyrrole-2-carboxamide; [0130]
5-Chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)-1H-pyrrole-2-carboxamide; [0131]
5-Chloro-N-((1-(4-(1,1-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methy-
l)thiophene-2-carboxamide; [0132]
5-Chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0133]
5-Chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; [0134]
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; [0135]
5-Chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0136]
5-Chloro-N-((1-(4-(3-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0137]
5-Chloro-N-((1-(4-(5-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0138]
5-Chloro-N-((1-(4-(4-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; [0139]
5-Chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-imi-
dazol-4-yl)methyl)thiophene-2-carboxamide [0140]
N-((1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl-
)-5-chlorothiophene-2-carboxamide; [0141]
5-Chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pheny-
l)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0142]
N-((1-(4-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)-5-chlorothiophene-2-carboxamide; [0143]
N-((1-(4-(4-acetamido-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)me-
thyl)-5-chlorothiophene-2-carboxamide; [0144]
5-Chloro-N-((1-(4-(2-oxopiperidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)th-
iophene-2-carboxamide; [0145]
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(piperidin-1-yl)ethoxy)phe-
nyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0146]
N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indol-
e-5-carboxamide; [0147]
5-Chloro-N-((2-(methylthio)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidaz-
ol-4-yl)methyl)thiophene-2-carboxamide; [0148]
5-Chloro-N-((2-(methylsulfonyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide; [0149]
5-Chloro-N-((2-(methylsulfinyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide; [0150]
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; [0151]
5-Chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-i-
midazol-4-yl)methyl)thiophene-2-carboxamide; [0152]
5-Chloro-N-((1-(4-(4-ethyl-2,3-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; [0153]
N-((1-(4-(2-(Carbamoylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)met-
hyl)-5-chlorothiophene-2-carboxamide; [0154]
5-Chloro-N-((2-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0155]
5-Chloro-N-((5-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0156]
5-Chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfin-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0157]
5-Chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfon-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0158]
5-Chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfin-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0159]
5-Chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfon-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0160]
5-Chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0161]
5-Chloro-N-((1-(2-(2-methoxyethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-i-
midazol-4-yl)methyl)thiophene-2-carboxamide; [0162]
(R)-5-Chloro-N-((1-(2-(2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phe-
nyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0163]
(S)-5-Chloro-N-((1-(2-(2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phe-
nyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0164]
5-Chloro-N-((1-(2-(2-hydroxypyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl-
)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0165]
5-Chloro-N-((1-(2-(6-hydroxypyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl-
)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide; [0166]
N-((1-(2-(6-Aminopyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidaz-
ol-4-yl)methyl)-5-chlorothiophene-2-carboxamide; [0167]
5-Chloro-N-((1-(4-(4-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0168]
5-Chloro-N-((1-(4-(6-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide; [0169]
5-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide; and [0170]
5-Chloro-N-((1-(4-(6-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide.
[0171] All of the preferred, more preferred, and most preferred
compounds listed above are selective inhibitors of Factor Xa.
[0172] b. Compositions
[0173] The present invention further provides compositions
comprising one or more compounds of formula (I) or a
pharmaceutically acceptable salt, ester or prodrug thereof, and a
pharmaceutically acceptable carrier. It will be appreciated that
the compounds of formula (I) in this invention may be derivatized
at functional groups to provide prodrug derivatives which are
capable of conversion back to the parent compounds in vivo.
Examples of such prodrugs include the physiologically acceptable
and metabolically labile ester derivatives, such as methoxymethyl
esters, methylthiomethyl esters, or pivaloyloxymethyl esters
derived from a hydroxyl group of the compound or a carbamoyl moiety
derived from an amino group of the compound. Additionally, any
physiologically acceptable equivalents of the compounds of formula
(I), similar to metabolically labile esters or carbamates, which
are capable of producing the parent compounds of formula (I) in
vivo, are within the scope of this invention.
[0174] If pharmaceutically acceptable salts of the compounds of
this invention are utilized in these compositions, those salts are
preferably derived from inorganic or organic acids and bases.
Included among such acid salts are the following: acetate, adipate,
alginate, aspartate, benzoate, benzene sulfonate, bisulfate,
butyrate, citrate, camphorate, camphor sulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate
and undecanoate. Base salts include ammonium salts, alkali metal
salts, such as sodium and potassium salts, alkaline earth metal
salts, such as calcium and magnesium salts, salts with organic
bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and
salts with amino acids such as arginine, lysine, and so forth.
[0175] Furthermore, the basic nitrogen-containing groups may be
quaternized with agents like lower alkyl halides, such as methyl,
ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl
sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates,
long chain halides, such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; aralkyl halides, such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0176] The compounds utilized in the compositions and methods of
this invention may also be modified by appending appropriate
functionalities to enhance selective biological properties. Such
modifications are known in the art and include those which increase
biological penetration into a given biological system (e.g., blood,
lymphatic system, central nervous system, etc.), increase oral
availability, increase solubility to allow administration by
injection, alter metabolism and alter rate of excretion.
[0177] The pharmaceutical compositions of the invention can be
manufactured by methods well known in the art such as conventional
granulating, mixing, dissolving, encapsulating, lyophilizing, or
emulsifying processes, among others. Compositions may be produced
in various forms, including granules, precipitates, or
particulates, powders, including freeze dried, rotary dried or
spray dried powders, amorphous powders, tablets, capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. Formulations may optionally contain stabilizers, pH
modifiers, surfactants, bioavailability modifiers and combinations
of these.
[0178] Pharmaceutical formulations may be prepared as liquid
suspensions or solutions using a sterile liquid, such as oil,
water, alcohol, and combinations thereof. Pharmaceutically suitable
surfactants, suspending agents or emulsifying agents, may be added
for oral or parenteral administration. Suspensions may include
oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and
olive oil. Suspension preparation may also contain esters of fatty
acids, such as ethyl oleate, isopropyl myristate, fatty acid
glycerides and acetylated fatty acid glycerides. Suspension
formulations may include alcohols, such as ethanol, isopropyl
alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers,
such as poly(ethyleneglycol), petroleum hydrocarbons, such as
mineral oil and petrolatum, and water may also be used in
suspension formulations.
[0179] Pharmaceutically acceptable carriers that may be used in
these compositions include ion exchangers, alumina, aluminum
stearate, lecithin, serum proteins, such as human serum albumin,
buffer substances, such as phosphates, glycine, sorbic acid,
potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0180] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being. Such pharmaceutical
compositions of the invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally,
buccally, vaginally or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. Preferably, the compositions are
administered orally or intravenously. The formulations of the
invention may be designed as short-acting, fast-releasing, or
long-acting. Still further, compounds can be administered in a
local rather than systemic means, such as administration (e.g.,
injection) as a sustained release formulation.
[0181] Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose, any bland fixed oil may be employed including synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its
glyceride derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as olive oil
or castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation. Compounds may be formulated for parenteral
administration by injection such as by bolus injection or
continuous infusion. A unit dosage form for injection may be in
ampoules or in multidose containers.
[0182] The pharmaceutical compositions of this invention may be in
any orally acceptable dosage form, including capsules, tablets,
aqueous suspensions or solutions. In the case of tablets for oral
use, carriers that are commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For a capsule form, useful diluents include
lactose and dried cornstarch. When aqueous suspensions are required
for oral use, the active ingredient is combined with emulsifying
and suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
[0183] Alternatively, the pharmaceutical compositions of this
invention may be in the form of suppositories for rectal
administration. These may be prepared by mixing the agent with a
suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0184] The pharmaceutical compositions of this invention may also
be in a topical form, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0185] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used. For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions may be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters, wax, cetyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0186] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative,
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment, such as petrolatum.
[0187] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons
and/or other conventional solubilizing or dispersing agents.
[0188] Any of the above dosage forms containing effective amounts
are within the bounds of routine experimentation and within the
scope of the invention. A therapeutically effective dose may vary
depending upon the route of administration and dosage form. The
preferred compound or compounds of the invention is a formulation
that exhibits a high therapeutic index. The therapeutic index is
the dose ratio between toxic and therapeutic effects which can be
expressed as the ratio between LD.sub.50 and ED.sub.50. The
LD.sub.50 is the dose lethal to 50% of the population and the
ED.sub.50 is the dose therapeutically effective in 50% of the
population. The LD.sub.50 and ED.sub.50 are determined by standard
pharmaceutical procedures in animal cell cultures or experimental
animals.
[0189] Besides those representative dosage forms described above,
pharmaceutically acceptable excipients and carriers and dosage
forms are generally known to those skilled in the art and are
included in the invention. It should be understood that a specific
dosage and treatment regimen for any particular patient will depend
upon a variety of factors, including the activity of the specific
compound employed, the age, body weight, general health, sex and
diet of the patient, and the time of administration, rate of
excretion, drug combination, judgment of the treating physician and
severity of the particular disease being treated. The amount of
active ingredient(s) will also depend upon the particular compound
and other therapeutic agent, if present, in the composition.
[0190] c. Methods of Use
[0191] The invention provides methods of inhibiting or decreasing
Factor Xa activity as well as treating or ameliorating a Factor Xa
associated state, symptom, disorder or disease in a patient in need
thereof (e.g., human or non-human). In one embodiment, the
invention provides methods for preventing or treating a condition
in a mammal characterized by undesired thrombosis comprising the
step of administering to the mammal a therapeutically effective
amount of a compound of the present invention. Such conditions
include, but are not limited, to acute coronary syndrome,
myocardial infarction, unstable angina, refractory angina,
occlusive coronary thrombus occurring post-thrombolytic therapy or
post-coronary angioplasty, a thrombotically mediated
cerebrovascular syndrome, embolic stroke, thrombotic stroke,
transient ischemic attacks, venous thrombosis, deep venous
thrombosis, pulmonary embolus, coagulopathy, disseminated
intravascular coagulation, thrombotic thrombocytopenic purpura,
thromboangiitis obliterans, thrombotic disease associated with
heparin-induced thrombocytopenia, thrombotic complications
associated with extracorporeal circulation, thrombotic
complications associated with instrumentation such as cardiac or
other intravascular catheterization, intra-aortic balloon pump,
coronary stent or cardiac valve, conditions requiring the fitting
of prosthetic devices, and the like.
[0192] "Treating" within the context of the invention means an
alleviation of symptoms associated with a disorder or disease, or
halt of further progression or worsening of those symptoms, or
prevention or prophylaxis of the disease or disorder.
[0193] The term "mammal" includes organisms which express Factor
Xa. Examples of mammals include mice, rats, cows, sheep, pigs,
goats, horses, bears, monkeys, dogs, cats and, preferably, humans.
Transgenic organisms which express Factor Xa are also included in
this definition.
[0194] The inventive methods comprise administering an effective
amount of a compound or composition described herein to a mammal or
non-human animal. As used herein, "effective amount" of a compound
or composition of the invention includes those amounts that
antagonize or inhibit Factor Xa. An amount which antagonizes or
inhibits Factor Xa is detectable, for example, by any assay capable
of determining Factor Xa activity, including the one described
below as an illustrative testing method. Effective amounts may also
include those amounts which alleviate symptoms of a Factor Xa
associated disorder treatable by inhibiting Factor Xa. Accordingly,
"antagonists of Factor Xa" include compounds which interact with
the Factor Xa and modulate, e.g., inhibit or decrease, the ability
of a second compound, e.g., another Factor Xa ligand, to interact
with the Factor Xa. The Factor Xa binding compounds are preferably
antagonists of Factor Xa. The language "Factor Xa binding compound"
(e.g., exhibits binding affinity to the receptor) includes those
compounds which interact with Factor Xa resulting in modulation of
the activity of Factor Xa. Factor Xa binding compounds may be
identified using an in vitro (e.g., cell and non-cell based) or in
vivo method. A description of an in vitro method is provided
below.
[0195] The amount of compound present in the methods and
compositions described herein should be sufficient to cause a
detectable decrease in the severity of the disorder, as measured by
any of the assays described in the examples. The amount of Factor
Xa modulator needed will depend on the effectiveness of the
modulator for the given cell type and the length of time required
to treat the disorder. In certain embodiments, the compositions of
this invention may further comprise another therapeutic agent. When
a second agent is used, the second agent may be administered either
as a separate dosage form or as part of a single dosage form with
the compounds or compositions of this invention. While one or more
of the inventive compounds can be used in an application of
monotherapy to treat a disorder, disease or symptom, they also may
be used in combination therapy, in which the use of an inventive
compound or composition (therapeutic agent) is combined with the
use of one or more other therapeutic agents for treating the same
and/or other types of disorders, symptoms and diseases. Combination
therapy includes administration of the two or more therapeutic
agents concurrently or sequentially. The agents may be administered
in any order. Alternatively, the multiple therapeutic agents can be
combined into a single composition that can be administered to the
patient. For instance, a single pharmaceutical composition could
comprise the compound or pharmaceutically acceptable salt, ester or
prodrug thereof according to the formula (I), another therapeutic
agent (e.g., methotrexate) or a pharmaceutically acceptable salt,
ester or prodrug thereof, and a pharmaceutically acceptable
excipient or carrier.
[0196] The invention comprises a compound having the formula (I), a
method for making an inventive compound, a method for making a
pharmaceutical composition from at least one inventive compound and
at least one pharmaceutically acceptable carrier or excipient, and
a method of using one or more inventive compounds to treat a
variety of disorders, symptoms and diseases (e.g., inflammatory,
autoimmune, neurological, neurodegenerative, oncology and
cardiovascular), such as RA, osteoarthritis, irritable bowel
disease IBD, asthma, chronic obstructive pulmonary disease COPD and
MS. The inventive compounds and their pharmaceutically acceptable
salts and/or neutral compositions may be formulated together with a
pharmaceutically acceptable excipient or carrier and the resulting
composition may be administered in vivo to mammals, such as men,
women and animals, to treat a variety of disorders, symptoms and
diseases. Furthermore, the inventive compounds can be used to
prepare a medicament that is useful for treating a variety of
disorders, symptoms and diseases.
[0197] d. Kits
[0198] Still another aspect of this invention is to provide a kit
comprising separate containers in a single package, wherein the
inventive pharmaceutical compounds, compositions and/or salts
thereof are used in combination with pharmaceutically acceptable
carriers to treat states, disorders, symptoms and diseases where
Factor Xa plays a role.
EXAMPLES
[0199] The starting materials and reagents used in preparing these
compounds generally are either available from commercial suppliers,
such as Aldrich Chemical Co., or are prepared by methods known to
those skilled in the art following procedures set forth in
references such as Fieser and Fieser's Reagents for Organic
Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22;
Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers,
1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley
& Sons: New York, 2005, Volumes 1-65.
[0200] The starting materials and the intermediates of the
synthetic reaction schemes can be isolated and purified if desired
using conventional techniques, including but not limited to,
filtration, distillation, crystallization, chromatography, and the
like. Such materials can be characterized using conventional means,
including physical constants and spectral data.
[0201] Unless specified to the contrary, the reactions described
herein preferably are conducted under an inert atmosphere at
atmospheric pressure at a reaction temperature range of from about
-78.degree. C. to about 150.degree. C., more preferably from about
0.degree. C. to about 125.degree. C., and most preferably and
conveniently at about room (or ambient) temperature, e.g., about
20.degree. C. to about 75.degree. C.
[0202] Referring to the examples that follow, compounds of the
present invention were synthesized using the methods described
herein, or other methods, which are well known in the art.
[0203] The compounds and/or intermediates were characterized by
high performance liquid chromatography (HPLC) using a Waters
Alliance chromatography system with a 2695 Separation Module
(Milford, Mass.). The analytical columns were C-18 SpeedROD RP-18E
Columns from Merck KGaA (Darmstadt, Germany). Alternately,
characterization was performed using a Waters Unity (HPLC) system
with Waters Acquity HPLC BEH C-18 2.1 mm.times.15 mm columns. A
gradient elution was used, typically starting with 5%
acetonitrile/95% water and progressing to 95% acetonitrile over a
period of 5 minutes for the Alliance system and 1 minute for the
Acquity system. All solvents contained 0.1% trifluoroacetic acid
(TFA). Compounds were detected by ultraviolet light (UV) absorption
at either 220 or 254 nm. HPLC solvents were from EMD Chemicals,
Inc. (Gibbstown, N.J.). In some instances, purity was assessed by
thin layer chromatography (TLC) using glass backed silica gel
plates, such as, for example, EMD Silica Gel 60 2.5 cm.times.7.5 cm
plates. TLC results were readily detected visually under
ultraviolet light, or by employing well known iodine vapor and
other various staining techniques.
[0204] Mass spectrometric analysis was performed on one of two
Agilent 1100 series LCMS instruments with acetonitrile/water as the
mobile phase. One system using TFA as the modifier and measures in
positive ion mode and the other uses either formic acid or ammonium
acetate and measures in both positive and negative ion modes.
[0205] Nuclear magnetic resonance (NMR) analysis was performed on
some of the compounds with a Varian 400 MHz NMR (Palo Alto,
Calif.). The spectral reference was either TMS or the known
chemical shift of the solvent.
[0206] The purity of some of the invention compounds may be
assessed by elemental analysis (Robertson Microlit, Madison
N.J.).
[0207] Melting points may be determined on a Laboratory Devices
MeI-Temp apparatus (Holliston, Mass.).
[0208] Preparative separations were carried out using either an
Sq16x or an Sg100c chromatography system and prepackaged silica gel
columns all purchased from Teledyne Isco, (Lincoln, Nebr.).
Alternately, compounds and intermediates were purified by flash
column chromatography using silica gel (230-400 mesh) packing
material, or by HPLC using a C-18 reversed phase column. Typical
solvents employed for the Isco systems and flash column
chromatography were dichloromethane, methanol, ethyl acetate,
hexane, acetone, aqueous hydroxyamine and triethyl amine. Typical
solvents employed for the reverse phase HPLC were varying
concentrations of acetonitrile and water with 0.1% trifluoroacetic
acid.
[0209] The following abbreviations are used throughout the
Examples: [0210] .mu.L=microliter [0211] .mu.M=micromolar [0212]
aq.=aqueous [0213]
BOP=benzotriazol-1-yloxytris(dimethylamino)-phosphonium
hexafluorophosphate [0214] CaCl.sub.2=calcium chloride [0215]
CH.sub.2Cl.sub.2=dichloromethane [0216] CH.sub.3CN=acetonitrile
[0217] CuI=copper iodide [0218] DIEA=diisopropyl ethyl amine [0219]
DMF=dimethyl formamide [0220] DMSO=dimethyl sulfoxide [0221]
EtOAc=ethyl acetate [0222] g=gram [0223] h=hour [0224]
HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate [0225] HPLC=high pressure liquid chromatography
[0226] IC.sub.50=The concentration of an inhibitor that is required
for 50% inhibition of an enzyme in vitro [0227] IV=intravenous
[0228] K.sub.2CO.sub.3=potassium carbonate [0229]
K.sub.3PO.sub.4=Potassium phosphate [0230] kg=kilogram [0231]
M=molar [0232] m/z=mass to charge ratio [0233]
mCPBA=m-chloroperoxybenzoic acid [0234] MeOH=methanol [0235]
mg=milligram [0236] MHz=Mega Hertz [0237] min=minute [0238]
mL=milliliter [0239] mm=millimeter [0240] mM=millimolar [0241]
mmol=millimole [0242] mOD/min=millioptical density units per minute
[0243] MP-=Macroporour triethylammonium methylpolystyrene carbonate
(0.5% carbonate inorganic antistatic agent) [0244] MS=Mass Spec
[0245] N=Normal [0246] NaCl=sodium chloride [0247] NaH=sodium
hydride [0248] NaHCO.sub.3=sodium bicarbonate [0249]
NaN.sub.3=sodium azide [0250] NaSMe=sodium methylthiolate [0251]
NaSO.sub.4=sodium sulfate [0252] nBuOH=n-butanol [0253] ng=nanogram
[0254] nm=nanometer [0255] nM=nanomolar [0256]
Pd(PPh.sub.3).sub.4=tetrakis-(triphenylphosphan)-palladium [0257]
PEG=polyethylene glycol [0258] pM=picomolar [0259] PO=oral [0260]
PPh.sub.3 or =triphenyl phosphine Ph.sub.3P [0261] Ra--Ni=Rainey
Nickel [0262] SOCl.sub.2=thionyl chloride [0263] TEA=triethylamine
[0264] TSC=trisodium citrate General Methods
[0265] The following synthetic reaction schemes are merely
illustrative of some methods by which the compounds of the present
invention can be synthesized, and various modifications to these
synthetic reaction schemes can be made and will be suggested to one
skilled in the art having referred to the disclosure contained in
this application. ##STR42##
[0266] Scheme I represents the general synthetic method for
preparing compounds having formula I-4. According to Scheme I, the
alcohol I-1 is transformed to the amine I-2 via a three-step
procedure: (1) halogenation such as with thionyl chloride, (2)
displacement of the halide with an azide such as sodium azide, and
(3) reduction of the azide to form the amine I-2 by catalytic
hydrogenation. The amine I-2 is then coupled with the acid Z--COOH
via conventional amide formation methods, such as using coupling
reagents like BOP, to form compound I-3, wherein Z is as defined
herein. Displacement of the iodo group of compound I-3 with the
corresponding R.sup.5 moiety, such as under basic conditions, such
as with K.sub.2CO.sub.3, and in the presence of 8-hydroxyquinoline
and CuI provides the desired compound I-4, wherein R.sup.5 is as
defined herein. Certain R.sup.5 moieties of compound I-4 may
undergo further modifications. For example, the thio group of
Example 6 may be oxidized to form the corresponding sulfoxide and
sulfone analogues. Compound I-1 may be obtained using either Scheme
1 or Scheme 2 below. ##STR43##
[0267] Compounds having formula II-7 may be prepared according to
Scheme II. (1H-imidazol-4-yl)methanol II-1 is converted to
(1H-imidazol-4-yl)methanamine II-2 via a three-step procedure and
coupled with Z--COOH to form compound II-3 using conditions similar
to that described above. Meanwhile, selective displacement of the
4-iodo group of 2-fluoro-1,4-diiodobenzene by R.sup.5--H such as
under basic conditions, such as with K.sub.2CO.sub.3, and in the
presence of 8-hydroxyquinoline and CuI provides compound II-5.
Subsequent displacement of the second iodo group with compound II-3
under similar conditions gives compound II-6. Compound II-6 may
also be prepared through a linear route as exemplified by Scheme 4
below. Displacement of the fluoro group with R.sup.4--H gives the
desired product II-7, wherein R.sup.4 is as defined herein.
Example 1
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)t-
hiophene-2-carboxamide (10)
[0268] Scheme 1 represents a synthetic method for the synthesis of
compound 10. Scheme 2 represents an alternative method for the
synthesis of compound I-1. ##STR44## ##STR45## Step 1:
[0269] A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol),
4-(hydroxymethyl)imidazole II-1 (1.20 g, 12.2 mmol),
8-hydroxyquinoline (0.176 g, 1.21 mmol) and K.sub.2CO.sub.3 (1.69
g, 12.2 mmol) in DMSO (12 mL) was degassed before being charged
with CuI (0.230 g, 1.21 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. Water and EtOAc were added. The
mixture was filtered. The organic layer was separated, then applied
to a silica gel column, which was eluted with 0-5% MeOH in
CH.sub.2Cl.sub.2 to give 4-hydroxymethyl 1-(4-iodophenyl)imidazole
I-1 (0.810 g). MS 301.2 (M+H).
Step 2:
[0270] The compound 4-hydroxymethyl I-(4-iodophenyl)imidazole I-1
(0.810 g, 2.70 mmol) was dissolved in SOCl.sub.2 (6 mL). The
solution was stirred at room temperature for 15 min. It was then
concentrated in vacuo. The residue was partitioned between EtOAc
and 5% aq. NaHCO.sub.3. The organic layer was separated, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give 4-chloromethyl
1-(4-iodophenyl)imidazole 1-3 as a solid (0.780 g). MS 318.9 and
320.9 (M+H, Cl pattern).
Step 3:
[0271] The compound 4-chloromethyl 1-(4-iodophenyl)imidazole 1-3
(0.780 g, 2.45 mmol) was dissolved in DMF (10 mL). To the solution,
NaN.sub.3 (0.520 g, 8.00 mmol) was added. After being stirred at
room temperature overnight, water and EtOAc were added. The organic
layer was separated, dried over Na.sub.2SO.sub.4, concentrated in
vacuo to give 4-azidomethyl 1-(4-iodophenyl)imidazole 1-4 as a
solid (0.725 g). MS 326.0 (M+H)
Step 4:
[0272] A solution of 4-azidomethyl 1-(4-iodophenyl)imidazole 1-4
(0.725 g, 2.23 mmol) over Ra--Ni (50% aq. slurry, 300 mg) in MeOH
(12 mL) was hydrogenated under balloon H.sub.2 for 3 h. The mixture
was filtrated through CELITE. The filtrate was concentrated in
vacuo to give 4-aminomethyl 1-(4-iodophenyl)imidazole I-2 as a
solid (0.603 g). MS 300.0 (M+H)
Step 5:
[0273] To a mixture of 5-chlorothiophene-2-carboxylic acid 1-5
(0.346 g, 2.13 mmol), 4-aminomethyl 1-(4-iodophenyl)imidazole I-2
prepared above (0.578 g, 1.93 mmol) and TEA (0.670 mL, 4.82 mmol)
in DMF (10 mL), BOP (1.03 g, 2.33 mmol) was added. The mixture was
then stirred at room temperature overnight. Water and EtOAc were
added. The organic layer was separated, washed with 5% NaHCO.sub.3,
dried over Na.sub.2SO.sub.4, concentrated in vacuo to give
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 as a solid (0.832 g), which was found to be pure enough
for next reaction. MS 443.9 and 445.9 (M+H, Cl pattern).
Step 6:
[0274] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared above (0.270 g, 0.609 mmol), 2-hydroxypyridine
1-7 (0.115 g, 1.21 mmol), 8-hydroxyquinoline (0.041 g, 0.283 mmol)
and K.sub.2CO.sub.3 (0.333 g, 2.41 mmol) in DMSO (2 mL) was
degassed before being charged with CuI (0.058 g, 0.305 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight.
The mixture was then purified by HPLC to give the title compound 10
(0.080 g). MS 411.0 and 413.0 (M+H, Cl pattern); .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 9.27 (m, 2H), 8.08 (s, 1H), 7.87
(d, 2H), 7.69 (d, 1H), 7.65 (m, 3H), 7.51 (m, 1H), 7.19 (d, 1H),
6.49 (d, 1H), 6.34 (dd, 1H), 4.52 (d, 2H).
Example 2
5-Chloro-N-((1-(4-(3-oxomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophe-
ne-2-carboxamide (11)
[0275] ##STR46##
[0276] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane.
To the flask, cooled in an ice-bath, a solution of ethanolamine
(4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was
heated at reflux for 10 min until no H.sub.2 gas evolved. The thick
slurry was then cooled in an ice-bath, and a solution of ethyl
chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The
reaction mixture was heated at reflux for 1 h. It was then
filtered. The filtrate was concentrated in vacuo to give an oil,
which was purified by a short silica gel column, eluted with
EtOAc/MeOH (95/5) to give 3-morpholinone as a white solid (1.9
g).
[0277] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared in Example 1 (33 mg, 0.074 mmol), 3-morpholinone
prepared above (22 mg, 0.218 mmol), 8-hydroxyquinoline (7 mg, 0.048
mmol) and K.sub.2CO.sub.3 (30 mg, 0.217 mmol) in DMSO (0.5 mL) was
degassed before being charged with CuI (14 mg, 0.073 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight.
The mixture was then purified by HPLC to give the title compound (3
mg). MS 417.0 and 419.0 (M+H, Cl pattern).
Example 3
5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)t-
hiophene-2-carboxamide (12)
[0278] ##STR47##
[0279] To a solution of glycinamide hydrochloride (1.10 g, 10.0
mmol) in 5 N NaOH (6 mL) at room temperature, glyoxal (40% in
H.sub.2O, 1.5 mL, 13.1 mmol) was added. The solution was stirred at
room temperature overnight. The product was extracted from the
aqueous solution with nBuOH, and the nBuOH extract was concentrated
in vacuo to give 2-hydroxypyrazine as a white solid (0.20 g).
[0280] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared in Example 1 (100 mg, 0.23 mmol),
2-hydroxypyrazine prepared above (43 mg, 0.45 mmol),
8-hydroxyquinoline (15 mg, 0.10 mmol) and K.sub.2CO.sub.3 (123 mg,
0.89 mmol) in DMSO (1 mL) was degassed before being charged with
CuI (21 mg, 0.11 mmol). The mixture in a sealed tube was heated at
130.degree. C. overnight. The mixture was then purified by HPLC to
give the title compound (15 mg). MS 412.0 and 414.0 (M+H, Cl
pattern).
Example 4
5-Chloro-N-((1-(4-(6-oxopyridazin-1(6H)-yl)phenyl)-1H-imidazol-4-yl)methyl-
)thiophene-2-carboxamide (13)
[0281] ##STR48##
[0282] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared in Example 1 (100 mg, 0.23 mmol),
3-hydroxypyridazine (43 mg, 0.45 mmol), 8-hydroxyquinoline (15 mg,
0.10 mmol) and K.sub.2CO.sub.3 (123 mg, 0.89 mmol) in DMSO (1 mL)
was degassed before being charged with CuI (19 mg, 0.10 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight.
The mixture was then purified by HPLC to give the title compound
(15 mg). MS 412.0 and 414.0 (M+H, Cl pattern).
Example 5
5-chloro-N-((1-(4-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (14)
[0283] ##STR49##
[0284] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (100 mg, 0.22 mmol), 2-hydroxy-6-methylpyridine (60 mg,
0.55 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol) and
K.sub.2CO.sub.3 (140 mg, 1.01 mmol) in DMSO (3 mL) was degassed
with Ar before being charged with CuI (28 mg, 0.15 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight.
The mixture was then purified by HPLC to give the titled compound
(4 mg). MS 425.1 and 427.1(M+H, Cl pattern).
Example 6
5-Chloro-N-((1-(4-(3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thi-
ophene-2-carboxamide (15)
[0285] ##STR50##
[0286] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared in Example 1 (230 mg, 0.518 mmol),
3-thiomorpholinone (121 mg, 1.03 mmol),
1,2-trans-diaminocyclohexane (26 .mu.L, 0.21 mmol) and
K.sub.3PO.sub.4 (220 mg, 1.04 mmol) in dioxane (2 mL) was degassed
with Ar before being charged with CuI (40 mg, 0.21 mmol). The
mixture in a sealed tube was heated at 110.degree. C. overnight. It
was then purified by HPLC to give the title compound (58 mg). MS
433.1 and 435.0 (M+H, Cl pattern).
Example 7
5-Chloro-N-((1-(4-(1,1-dioxo-3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)-
methyl)thiophene-2-carboxamide (16) and
5-Chloro-N-((1-(4-(1,3-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methy-
l)thiophene-2-carboxamide (17)
[0287] ##STR51##
[0288] To a solution of
5-chloro-N-((1-(4-(3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)th-
iophene-2-carboxamide prepared in Example 6 (56 mg, 0.13 mmol) in
acetone (3 mL) at room temperature, mCPBA (38 mg, 70-77%, 0.15
mmol) was added. It was stirred at room temperature for 1 h. HPLC
showed formation of the sulfone and sulfoxide in a ratio of 2 to 1.
The solution was concentrated in vacuo, and the residue was
purified by HPLC to give the sulfone (6 mg) and the sulfoxide (3
mg). MS 465.0 and 467.0 (M+H, Cl pattern) for the sulfone and 449.1
and 451.0 (M+H, Cl pattern) for the sulfoxide.
Example 8
5-Chloro-N-((1-(4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol--
4-yl)methyl)thiophene-2-carboxamide (18)
[0289] ##STR52##
[0290] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared in Example 1 (80 mg, 0.18 mmol),
tetrahydro-2-pyrimidinone (54 mg, 0.54 mmol),
1,2-trans-diaminocyclohexane (13 .mu.L, 0.11 mmol) and
K.sub.3PO.sub.4 (100 mg, 0.47 mmol) in dioxane (1 mL) was degassed
with Ar before being charged with CuI (20 mg, 0.11 mmol). The
mixture in a sealed tube was heated at 110.degree. C. overnight. It
was then purified by HPLC to give the title compound (4 mg). MS
416.1 and 418.1 (M+H, Cl pattern).
Example 9
5-Chloro-N-((1-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)-
thiophene-2-carboxamide (19)
[0291] ##STR53##
[0292] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared in Example 1 (80 mg, 0.18 mmol), ethyleneurea (40
mg, 0.47 mmol), 1,2-trans-diaminocyclohexane (15 .mu.L, 0.12 mmol)
and K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed
with Ar before being charged with CuI (20 mg, 0.11 mmol). The
mixture in a sealed tube was heated at 110.degree. C. overnight. It
was then purified by HPLC to give the title compound (5 mg). MS
402.1 and 404.1 (M+H, Cl pattern).
Example 10
5-Chloro-N-((1-(4-(2,5-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4-yl)methyl-
)thiophene-2-carboxamide (20)
[0293] ##STR54##
[0294] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 prepared in Example 1 (80 mg, 0.18 mmol), glycine
anhydride (40 mg, 0.35 mmol), 1,2-trans-diaminocyclohexane (30
.mu.L, 0.24 mmol) and K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO
(1 mL) was degassed with Ar before being charged with CuI (20 mg,
0.11 mmol). The mixture in a sealed tube was heated at 110.degree.
C. overnight. It was then purified by HPLC to give the title
compound (10 mg). MS 430.1 and 432.1 (M+H, Cl pattern).
Example 11
5-Chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (21)
[0295] ##STR55## ##STR56##
[0296] A mixture of 2,5-diiodofluorobenzene II-4 (2.00 g, 5.75
mmol), 2-hydroxypyridine 1-7 (0.546 g, 5.75 mmol),
8-hydroxyquinoline (0.083 g, 0.57 mmol) and K.sub.2CO.sub.3 (1.00
g, 7.25 mmol) in DMSO (10 mL) was degassed before being charged
with CuI (0.109 g, 0.57 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. Water and EtOAc were added. The
mixture was filtered. The organic layer was separated, then applied
to a silica gel column, which was eluted with 0-70% EtOAc in hexane
to give 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 (0.820
g). MS 315.8 (M+H).
[0297] To a suspension of 4-hydroxymethylimidazole II-1 (1.09 g,
11.1 mmol) in CH.sub.3CN (12 mL), SOCl.sub.2 (5 mL) was added.
After being stirred at room temperature for 30 min, the suspension
became clear. After stirring for additional 2 h, the solution was
concentrated in vacuo to give a solid, which was then dissolved in
DMF (15 mL). To the solution, NaN.sub.3 (2.16 g, 33.2 mmol) was
added. After the mixture was stirred at room temperature overnight,
water and EtOAc were added, then 5% aq. NaHCO.sub.3 was also added.
The organic layer was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give 4-azidomethylimidazole as a solid
(0.759 g). MS 124.1 (M+H).
[0298] A mixture of 4-azidomethylimidazole prepared above (0.759 g,
6.17 mmol) and Ra--Ni (50% slurry in H.sub.2O, 900 mg) in MeOH (15
mL) was hydrogenated under H.sub.2 balloon overnight. The mixture
was then filtered through CELITE. The filtrate was concentrated in
vacuo to give 4-aminomethylimidazole II-2 (0.604 g).
[0299] To a solution of 5-chlorothiophene-2-carboxylic acid
1-5(1.10 g, 6.76 mmol) and TEA (2.0 mL, 14.4 mmol) in DMF (12 mL),
BOP (3.30 g, 7.45 mmol) was added. After being mixed for 5 min, the
solution was added to the compound 4-aminomethylimidazole II-2
prepared above (0.604 g, 6.22 mmol) in a round bottom flask. The
mixture was then stirred at room temperature overnight. It was
purified by HPLC to give
5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1
(1.52 g). MS 242.0 and 244.0 (M+H, Cl pattern).
[0300] A mixture of
5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1
prepared above (0.940 g, 2.64 mmol),
1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared above
(0.820 g, 2.60 mmol), 8-hydroxyquinoline (0.066 g, 0.45 mmol) and
K.sub.2CO.sub.3 (0.630 g, 4.56 mmol) in DMSO (8 mL) was degassed
with Ar before being charged with CuI (0.090 g, 0.47 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give the title compound (0.480 g). MS
429.0 and 431.0 (M+H, Cl pattern).
[0301] Alternatively as shown in Scheme
4,1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared as
above, is treated with 4-hydroxymethylimidazole II-1 in the
presence of 8-hydroxyquinoline, and K.sub.2CO.sub.3 in DMSO. The
resulting mixture is degassed before being charged with CuI to give
4-hydroxymethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole
4-1. The compound 4-1 is treated with thionyl chloride to give
4-chloromethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole
which is then treated with NaN.sub.3 to result in
4-azidomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole
4-2. The azide 4-2 is reduced with Ph.sub.3P to give
4-aminomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole
4-3. The compound 4-3 is then treated with
5-chlorothiophene-2-carboxylic acid 1-5 to give the title compound
21.
Example 12
5-Chloro-N-((1-(2-(methylsulfonyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imi-
dazol-4-yl)methyl)thiophene-2-carboxamide (22) and
5-chloro-N-((1-(2-(methylsulfinyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide (23)
[0302] ##STR57##
[0303] A solution of
5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide 21 prepared in Example 11 (96 mg,
0.22 mmol) and NaSMe (68 mg, 0.97 mmol) in DMSO (2 mL) was heated
at 80.degree. C. for 1 h. The mixture was purified by HPLC to give
5-chloro-N-((1-(2-(methylthio)-4-(2
oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxami-
de (16 mg). MS 457.0 and 459.0 (M+H, Cl pattern)
[0304] To a solution of
5-chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidaz-
ol-4-yl)methyl)thiophene-2-carboxamide prepared above (16 mg, 0.035
mmol) in acetone (1 mL), mCPBA (70%, 12 mg, 0.049 mmol) was added.
After being stirred at room temperature for 30 min, the mixture was
purified by HPLC to give the sulfoxide (5 mg) and sulfone (3 mg).
MS 473.0 and 475.0 (M+H, Cl pattern) for sulfoxide and 489.0 and
491.0 (M+H, Cl pattern) for sulfone.
Example 13
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-thiomorpholinophenyl)-1H-imida-
zol-4-yl)methyl)thiophene-2-carboxamide (24)
[0305] ##STR58##
[0306] A solution of
5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide prepared in Example 11 (70 mg,
0.16 mmol) and thiomorpholine (1 mL) in DMSO (1 mL) was heated at
150.degree. C. for 3 days. The mixture was purified by HPLC to give
the title compound (25 mg). MS 512.0 and 514.0 (M+H, Cl
pattern).
Example 14
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(1,1-dioxo-thiomorpholin-4-yl)-
phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (25)
[0307] ##STR59##
[0308] To a solution of
5-chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-thiomorpholinophenyl)-1H-imid-
azol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 13 (22
mg, 0.043 mmol) in acetone (2 mL), mCPBA (70%, 32 mg, 0.13 mmol)
was added. After being stirred at room temperature for 2 h, the
mixture was purified by HPLC to give the title compound (8 mg). MS
544.1 and 546.1 (M+H, Cl pattern).
Example 15
5-Chloro-N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1-
H-imidazol-4-yl)methyl)thiophene-2-carboxamide (26)
[0309] ##STR60##
[0310] A solution of
5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide prepared in Example 11 (70 mg,
0.16 mmol) and 2-oxopiperazine (565 mg, 5.65 mmol) in DMSO (1 mL)
was heated at 150.degree. C. for 2 days. The mixture was purified
by HPLC to give the title compound (14 mg). MS 509.0 and 511.0
(M+H, Cl pattern).
Example 16
5-Chloro-N-((1-(2-(2-hydroxyethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1-
H-imidazol-4-yl)methyl)thiophene-2-carboxamide (27)
[0311] ##STR61##
[0312] A solution of
5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide prepared in Example 11 (75 mg,
0.17 mmol) and ethanolamine (1.5 mL) in DMSO (1 mL) in a sealed
tube was heated at 150.degree. C. overnight. The mixture was
purified by HPLC to give the title compound (13 mg). MS 470.0 and
472.0 (M+H, Cl pattern).
Example 17
5-Chloro-N-((1-(2-hydroxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide (28)
[0313] ##STR62##
[0314] A solution of
5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide prepared in Example 11 (80 mg,
0.19 mmol) and 5 N aq. NaOH (0.5 mL, 2.5 mmol) in DMSO (2 mL) in a
sealed tube was heated at 130.degree. C. overnight. The mixture was
purified by HPLC to give the title compound (5 mg). MS 427.0 and
429.0 (M+H, Cl pattern).
Example 18
5-Chloro-N-((1-(2-methoxycarbonyl-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imid-
azol-4-yl)methyl)thiophene-2-carboxamide (29)
[0315] ##STR63##
[0316] To a solution of 2,5-diiodobenzoic acid (1.00 g, 2.67 mmol)
in anhydrous MeOH (15 mL) cooled in an ice-bath, SOCl.sub.2 (0.50
mL, 6.85 mmol) was cautiously added (exothermal reaction). After
the addition, the solution was heated at reflux overnight. It was
then concentrated in vacuo to give methyl 2,5-diiodobenzoate (1.04
g).
[0317] A mixture of methyl 2,5-diiodobenzoate prepared above (1.04
g, 2.67 mmol), 2-hydroxypyridine 1-7 (0.254 g, 2.67 mmol),
8-hydroxyquinoline (0.077 g, 0.53 mmol) and K.sub.3PO.sub.4 (1.13
g, 5.33 mmol) in dioxane (8 mL) was degassed with Ar before being
charged with CuI (0.101 g, 0.53 mmol). The mixture in a sealed tube
was heated at 130.degree. C. overnight. It was then purified by
HPLC to give 2-iodo-5-(2-oxopyridin-1(2H)-yl)benzoic acid (0.220
g). MS 342.0 (M+H).
[0318] A mixture of 2-iodo-5-(2-oxopyridin-1(2H)-yl)benzoic acid
prepared above (220 mg, 0.65 mmol), 4-hydroxymethylimidazole II-1
(126 mg, 1.29 mmol), 8-hydroxyquinoline (19 mg, 0.13 mmol) and
K.sub.2CO.sub.3 (290 mg, 2.10 mmol) in DMSO (2 mL) was degassed
with Ar before being charged with CuI (25 mg, 0.13 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give
2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoic
acid (92 mg). MS 312.1 (M+H).
[0319] To a solution of
2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoic
acid prepared above (92 mg, 0.30 mmol) in MeOH (4 mL) and dioxane
(2 mL) at room temperature, (trimethylsilyl)diazomethane (2 M in
ether, 0.30 mL, 0.60 mmol) was added. After the mixture was stirred
at room temperature overnight, more (trimethylsilyl)diazomethane (2
M in ether, 0.40 mL, 0.80 mmol) was added. After stirring for
another day, the solution was concentrated in vacuo to give a
residue. The residue was dissolved in SOCl.sub.2 (4 mL). The
solution was stirred at room temperature for 20 min before it was
concentrated in vacuo to give a residue, which was then dissolved
in DMF (3 mL). To the solution, NaN.sub.3 (65 mg, 1.0 mmol) was
added. After the mixture was stirred at room temperature for 2 h,
water and EtOAc were added, then 5% aq. NaHCO.sub.3 was added. The
organic layer was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give methyl
2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate
(25 mg). MS 351.1 (M+H).
[0320] To a solution of methyl
2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate
prepared above (25 mg, 0.071 mmol) in THF (1 mL) and H.sub.2O
(0.025 mL, 1.4 mmol), Ph.sub.3P (64 mg, 0.24 mmol) was added. After
being stirred at room temperature overnight, the mixture was
concentrated in vacuo to give methyl
2-(4-(aminomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benz-
oate as a crude mixture, which was then used in the next
transformation. MS 325.1 (M+H).
[0321] To a solution of 5-chlorothiophene-2-carboxylic acid 1-5 (40
mg, 0.25 mmol) and TEA (0.068 mL, 0.49 mmol) in DMF (2 mL), BOP
(142 mg, 0.32 mmol) was added. After 5 min of mixing, the solution
was added to the sample methyl
2-(4-(aminomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate
prepared above. The mixture was then stirred at room temperature
for 1 h before it was purified by HPLC to give the title compound
(4 mg). MS 469.0 and 471.0 (M+H, Cl pattern).
Example 19
5-Chloro-N-((1-(4-(2-thioxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methy-
l)thiophene-2-carboxamide (30)
[0322] ##STR64##
[0323] A mixture of 1,4-diiodobenzene 1-1 (2.00 g, 6.06 mmol),
2-hydroxypyridine 1-7 (0.576 g, 6.06 mmol), 8-hydroxyquinoline
(0.088 g, 0.61 mmol) and K.sub.2CO.sub.3 (0.870 g, 6.30 mmol) in
DMSO (8 mL) was degassed with Ar before being charged with CuI
(0.115 g, 0.61 mmol). The mixture in a sealed tube was heated at
130.degree. C. overnight. Water and EtOAc were added. The mixture
was filtered through CELITE. The organic layer was separated, then
applied to a silica gel column, which was eluted with 0-70% EtOAc
in hexane to give 1-(4-iodophenyl)pyridin-2(1H)-one as a solid
(0.760 g). MS 298.0 (M+H).
[0324] A mixture of 1-(4-iodophenyl)pyridin-2(1H)-one prepared
above (0.760 g, 2.56 mmol), NaHCO.sub.3 (2.15 g, 25.6 mmol) and
P.sub.2S.sub.5 (2.27 g, 10.2 mmol) in dioxane (20 mL) was heated at
80.degree. C. overnight. After being cooled to room temperature,
water and CH.sub.2Cl.sub.2 were added. The organic layer was
separated, washed with brine, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give 1-(4-iodophenyl)pyridine-2(1H)-thione
as a solid (0.752 g). MS 313.8 (M+H).
[0325] A mixture of 1-(4-iodophenyl)pyridine-2(1H)-thione prepared
above (65 mg, 0.21 mmol),
5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1
prepared in Example 11 (65 mg, 0.18 mmol), 8-hydroxyquinoline (10
mg, 0.069 mmol) and K.sub.2CO.sub.3 (75 mg, 0.54 mmol) in DMSO (2
mL) was degassed with Ar before being charged with CuI (27 mg, 0.14
mmol). The mixture in a sealed tube was heated at 130.degree. C.
overnight. It was then purified by HPLC to give the title compound
(15 mg). MS 427.0 and 429.0 (M+H, Cl pattern).
Example 20
N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indole-
-6-carboxamide (31)
[0326] ##STR65##
[0327] To a solution of indole-6-carboxylic acid (85 mg, 0.528
mmol), 4-aminomethyl 1-(4-iodophenyl)imidazole I-2 prepared in
Example 1 (136 mg, 0.455 mmol) and TEA (0.150 mL, 1.08 mmol) in DMF
(4 mL), BOP (280 mg, 0.633 mmol) was added. After the mixture was
stirred at room temperature overnight, water and EtOAc were added.
The organic layer was separated, washed with 5% aq. NaHCO.sub.3,
dried over Na.sub.2SO.sub.4, concentrated in vacuo to give
N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide
as a crude sample, which was used in the next reaction without
further purification. MS 443.0 (M+H).
[0328] A mixture of
N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide
prepared above, 2-hydroxypyridine 1-7 (130 mg, 1.37 mmol),
8-hydroxyquinoline (30 mg, 0.21 mmol) and K.sub.2CO.sub.3 (246 mg,
1.78 mmol) in DMSO (2 mL) was degassed before being charged with
CuI (43 mg, 0.23 mmol). The mixture in a sealed tube was heated at
130.degree. C. overnight. It was then purified by HPLC to give the
title compound (50 mg). MS 410.1 (M+H).
Example 21
5-Ethynyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-
thiophene-2-carboxamide (32)
[0329] ##STR66##
[0330] A mixture of ethyl 5-bromo-thiophene-2-carboxylate (500 mg,
2.13 mmol), trimethylsilylacetylene (0.445 mL, 3.2 mmol),
Pd(PPh.sub.3).sub.4 (15 mg) and CuI (10 mg) in diisopropylamine (10
mL) was heated at 80.degree. C. for 2 h. After being cooled to room
temperature, the mixture was filtered through CELITE, and the
filtrate was poured into water. The product was extracted with
EtOAc. The EtOAc solution was washed with brine, dried over
MgSO.sub.4, concentrated in vacuo to give ethyl
5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate (529 mg).
MS 253 (M+H).
[0331] To a solution of ethyl
5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate prepared
above (529 mg, 2.10 mmol) in THF (20 mL), 1N aq. LiOH (7.0 mL, 7.0
mmol) was added. After the mixture was stirred at 40.degree. C.
overnight, it was poured into water. The aqueous solution was
acidified with 1 N HCl to pH 1. The product was extracted with
EtOAc. The EtOAc solution was washed with brine, dried over
MgSO.sub.4, concentared in vacuo to give
5-ethynyl-thiophene-2-carboxylic acid (316 mg). MS 153 (M+H).
[0332] A mixture of 1-(4-iodophenyl)pyridin-2(1H)-one prepared in
Example 19 (1.00 g, 3.37 mmol), 4-hydroxymethylimidazole II-1
(0.330 g, 3.37 mmol), 8-hydroxyquinoline (0.073 g, 0.50 mmol) and
K.sub.2CO.sub.3 (1.00 g, 7.25 mmol) in DMSO (7 mL) was degassed
with Ar before being charged with CuI (0.100 g, 0.52 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight.
Water and EtOAc were added. The mixture was filtered through
CELITE. The organic layer was separated, dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified
by HPLC to give
1-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
(335 mg). MS 268 (M+H).
[0333] To a suspension of
1-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
prepared above (335 mg, 1.25 mmol) in CH.sub.3CN (20 mL),
SOCl.sub.2 (5.0 mL) was added. After the mixture was stirred at
room temperature for 2 h, it was concentrated in vacuo. The residue
was then dissolved in DMF (20 mL). To the solution, NaN.sub.3 (244
mg, 3.75 mmol) was added. After the mixture was stirred at room
temperature overnight, water and EtOAc were added. The organic
layer was separated, washed with 5% aq. NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give
1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
(203 mg). MS 293 (M+H).
[0334] To a solution of
1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
prepared above (203 mg, 0.695 mmol) in MeOH (6 mL) and EtOAc (6
mL), SnCl.sub.2 2H.sub.2O (343 mg, 1.52 mmol) was added. After the
mixture was heated to reflux for 1 h, it was concentrated in vacuo.
The residue was purified by HPLC to give
1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
(145 mg). MS 267 (M+H).
[0335] To a solution of 5-ethynyl-thiophene-2-carboxylic acid (83
mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF (4 mL), HATU (228
mg, 0.60 mmol) was added. After being stirred at room temperature
for 30 min, a solution of
1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
prepared above (145 mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in
DMF (8 mL) was added. The mixture was stirred at room temperature
overnight. It was then purified by HPLC to give the title compound
(65 mg). MS 401 (M+H).
Example 22
(E)-5-chloro-N-((1-(4-(2-(cyanoimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol--
4-yl)methyl)thiophene-2-carboxamide (33)
[0336] ##STR67##
[0337] To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (180
mg, 0.575 mmol) in CH.sub.3CN (15 mL), CH.sub.3I (0.50 mL, 8.0
mmol) was added. After being stirred at room temperature overnight,
the mixture was concentrated in vacuo to give a solid. The solid
was dissolved in CH.sub.3CN (5 mL). To the solution, cyanamide (200
mg, 4.76 mmol) and hydrazine monohydrate (0.100 mL, 2.06 mmol) were
added. After being stirred at room temperature for 2 h, the mixture
was purified by HPLC to give
(E)-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)cyanamide (25 mg).
[0338] A mixture of
(E)-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)cyanamide (25 mg, 0.078
mmol), 5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide
3-1 (65 mg, 0.18 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (75 mg, 0.54 mmol) in DMSO (1 mL) was degassed with
Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture
in a sealed tube was heated at 130.degree. C. overnight. It was
then purified by HPLC to give the titled compound (10 mg). MS 435.1
and 437.0 (M+H, Cl pattern).
Example 23
(E)-5-chloro-N-((1-(4-(2-(methylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-
-4-yl)methyl)thiophene-2-carboxamide (34)
[0339] ##STR68##
[0340] To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (98
mg, 0.31 mmol) in CH.sub.3CN (5 mL), CH.sub.3I (0.25 mL, 4.0 mmol)
was added. After being stirred at room temperature overnight, the
mixture was concentrated in vacuo to give a solid. The solid was
dissolved in MeOH (7 mL). To the solution, CH.sub.3NH.sub.2 (2M in
THF, 0.80 mL, 1.6 mmol) was added. After being stirred at room
temperature overnight, the mixture was purified by HPLC to give
(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)methanamine (59
mg).
[0341] A mixture of
(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)methanamine (59 mg,
0.14 mmol),
5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1
(63 mg, 0.18 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed
with Ar before being charged with CuI (15 mg, 0.079 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give the titled compound (15 mg). MS
424.1 and 426.1 (M+H, Cl pattern).
Example 24
(E)-5-chloro-N-((1-(4-(2-(4-methoxyphenylimino)pyridin-1(2H)-yl)phenyl)-1H-
-imidazol-4-yl)methyl)thiophene-2-carboxamide (35)
[0342] ##STR69##
[0343] To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (192
mg, 0.61 mmol) in CH.sub.3CN (5 mL), CH.sub.3I (0.40 mL, 6.4 mmol)
was added. After being stirred at room temperature overnight, the
mixture was concentrated in vacuo to give a solid. The solid was
dissolved in DMF (3 mL). To the solution, p-anisidine (317 mg, 2.6
mmol) was added. After being stirred at 100.degree. C. overnight,
the mixture was purified by HPLC to give
(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)-4-methoxybenzenamine
(90 mg).
[0344] A mixture of
(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)-4-methoxybenzenamine
(90 mg, 0.17 mmol),
5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1
(62 mg, 0.17 mmol), 8-hydroxyquinoline (14 mg, 0.096 mmol) and
K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO (2 mL) was degassed
with Ar before being charged with CuI (20 mg, 0.10 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give the titled compound (25 mg). MS
516.0 and 518.1 (M+H, Cl pattern).
Example 25
(E)-N-((1-(4-(2-(acetylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)met-
hyl)-5-chlorothiophene-2-carboxamide (36)
[0345] ##STR70##
[0346] To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (384
mg, 1.23 mmol) in CH.sub.3CN (10 mL), CH.sub.3I (0.80 mL, 12.8
mmol) was added. After being stirred at room temperature overnight,
the mixture was concentrated in vacuo to give a solid. The solid
was dissolved in DMF (6 mL). To the solution, NH.sub.3 in MeOH (7N,
3.0 mL, 21.0 mmol) and triethylamine (1.5 mL, 10.8 mmol) were
added. After being stirred at room temperature overnight, the
mixture was purified by HPLC to give a solid. The solid was
dissolved in pyridine (3 mL) and CH.sub.2Cl.sub.2 (3 mL). To the
solution, acetyl chloride (0.200 mL, 2.8 mmol) was added. After
being stirred at room temperature overnight, the mixture was
purified by HPLC to give
(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)acetamide (120
mg).
[0347] A mixture of
(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)acetamide (120 mg,
0.27 mmol),
5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1
(109 mg, 0.30 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and
K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO (2 mL) was degassed
with Ar before being charged with CuI (24 mg, 0.12 mmol). The
mixture in a sealed tube was heated at 130.degree. C. for 5 h. It
was then purified by HPLC to give the titled compound (8 mg). MS
452.0 and 454.0 (M+H, Cl pattern).
Example 26
4-chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)-1H-pyrrole-2-carboxamide (37)
[0348] ##STR71##
[0349] A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol),
2-hydroxypyridine 1-7 (1.15 g, 12.1 mmol), 8-hydroxyquinoline (176
mg, 1.21 mmol) and K.sub.2CO.sub.3 (1.74 g, 12.6 mmol) in DMSO (16
mL) was degassed with Ar before being charged with CuI (230 mg,
1.21 mmol). The mixture in a sealed tube was heated at 130.degree.
C. overnight. After being cooled to room temperature, H.sub.2O and
EtOAc were added. It was filtered through celite. The organic phase
was separated, dried over Na.sub.2SO.sub.4, concentrated in vacuo.
The residue was purified by a silica gel column, eluted with EtOAc
in hexanes (0-70% EtOAc) to give 1-(4-iodophenyl)pyridin-2(1H)-one
(1.30 g).
[0350] To a solution of 1-methyl-2-pyrrolecarboxylic acid (1.03 g,
8.22 mmol) in MeOH (5 mL) and dioxane (5 mL) at room temperature,
trimethylsilyldiazomethane (2M in ether, 5.0 mL, 10.0 mmol) was
added. After being stirred at room temperature for 1 h, the mixture
was concentrated in vacuo to give methyl
1-methyl-2-pyrrolecarboxylate as a volatile oil (1.14 g).
[0351] To a solution of methyl 1-methyl-2-pyrrolecarboxylate (1.14
g, 8.22 mmol) in ether (10 mL) at 0.degree. C., SO.sub.2Cl.sub.2
(0.800 mL, 9.96 mmol) was added. After being stirred at room
temperature for 15 min, the mixture was concentrated in vacuo. The
residue was purified by a silica gel column, eluted with 5% EtOAc
in hexane to give methyl 4-chloro-1-methyl-1H-pyrrole-2-carboxylate
(0.13 g). The fractions containing methyl
5-chloro-1-methyl-1H-pyrrole-2-carboxylate were further purified by
HPLC to give the 5-chloro-isomer.
[0352] To a solution of methyl
4-chloro-1-methyl-1H-pyrrole-2-carboxylate (130 mg, 0.75 mmol) in
MeOH (4 mL), aq. 1 N NaOH (3 mL) was added. After being stirred at
room temperature overnight, the mixture was acidified with 1 N HCl
to pH 1-2. The product was extracted with EtOAc. The EtOAc phase
was separated, dried over Na.sub.2SO.sub.4, concentrated in vacuo
to give 4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid as a solid
(111 mg).
[0353] To a solution of 4-chloro-1-methyl-1H-pyrrole-2-carboxylic
acid (55 mg, 0.34 mmol) and triethylamine (0.100 mL, 0.72 mmol) in
DMF (2 mL), BOP (217 mg, 0.49 mmol) was added. After 5 min of
stirring, a solution of 4-aminomethylimidazole II-2 (100 mg, 1.03
mmol) in DMF (2 mL) was added. After being stirred at room
temperature overnight, the mixture was purified by HPLC to give
N-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide
(81 mg).
[0354] A mixture of
N-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide
(81 mg, 0.23 mmol), 1-(4-iodophenyl)pyridin-2(1H)-one (100 mg, 0.33
mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K.sub.2CO.sub.3
(193 mg, 1.40 mmol) in DMSO (2 mL) was degassed with Ar before
being charged with CuI (21 mg, 0.11 mmol). The mixture in a sealed
tube was heated at 130.degree. C. overnight. It was then purified
by HPLC to give the titled compound (25 mg). MS 408.1 and 410.1
(M+H, Cl pattern).
Example 27
5-chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)-1H-pyrrole-2-carboxamide (38)
[0355] ##STR72##
[0356] The titled compound was prepared analogously to preparation
of
4-chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)-1H-pyrrole-2-carboxamide of Example 26. MS 408.1 and
410.1 (M+H, Cl pattern).
Example 28
5-chloro-N-((1-(4-(1,1-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl-
)thiophene-2-carboxamide (39)
[0357] ##STR73##
[0358] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (56 mg, 0.10 mmol), 1,4-butanesultam (52 mg, 0.38 mmol),
8-hydroxyquinoline (6 mg, 0.040 mmol) and K.sub.2CO.sub.3 (50 mg,
0.36 mmol) in DMSO (1 mL) was degassed before being charged with
CuI (10 mg, 0.052 mmol). The mixture in a sealed tube was heated at
130.degree. C. overnight. The mixture was then purified by HPLC to
give the titled compound (10 mg). MS 451.1 and 453.1 (M+H, Cl
pattern).
Example 29
5-chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (40)
[0359] ##STR74##
[0360] A mixture of 2,5-diiodofluorobenzene II-4 (2.50 g, 7.18
mmol), 4-hydroxymethylimidazole hydrochloride (0.967 g, 7.18 mmol),
8-hydroxyquinoline (0.104 g, 0.717 mmol) and K.sub.2CO.sub.3 (2.00
g, 14.5 mmol) in DMSO (12 mL) was degassed with Ar before being
charged with CuI (0.136 g, 0.716 mmol). The mixture in a sealed
tube was heated at 130.degree. C. overnight. After being cooled to
room temperature, H.sub.2O and EtOAc were added. It was filtered
through celite. The organic phase was separated, dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified
by a silica gel column, eluted with MeOH in CH.sub.2Cl.sub.2 (0-5%
MeOH) to give (1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanol
(0.39 g).
[0361] To a suspension of
(1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanol (0.39 g, 1.23
mmol) in CH.sub.3CN (7 mL), SOCl.sub.2 (2.5 mL) was added. Upon the
addition, the suspension became clear. It was then concentrated in
vacuo. The residue was dissolved in DMF (7 mL), NaN.sub.3 (0.32 g,
4.92 mmol) was added. The mixture was stirred at room temperature
overnight. H.sub.2O and EtOAc were added. The organic phase was
separated, washed with 5% NaHCO.sub.3, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was dissolved in MeOH (6 mL),
Ra--Ni (50% slurry in H.sub.2O, .about.200 mg) was added. The
mixture was hydrogenated under balloon H.sub.2 for 2 h. It was then
filtered through celite. The filtrate was concentrated in vacuo to
give (1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanamine as a
solid (0.268 g).
[0362] To a solution of 5-chloro-2-thiophenecarboxylic acid 1-5
(165 mg, 1.01 mmol) and triethylamine (0.300 mL, 2.16 mmol) in DMF
(5 mL), BOP (472 mg, 1.07 mmol) was added. After 5 min of stirring,
a solution of
(1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanamine (268 mg,
0.845 mmol) in DMF (4 mL) was added. The mixture was stirred at
room temperature overnight. H.sub.2O and EtOAc were added. The
organic phase was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified
by HPLC to give
5-chloro-N-((1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene--
2-carboxamide (83 mg).
[0363] A mixture of
5-chloro-N-((1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene--
2-carboxamide (83 mg, 0.14 mmol), 2-hydroxypyridine 1-7 (30 mg,
0.31 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with
Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture
was heated at 130.degree. C. in a sealed tube for 4 h. It was then
purified by HPLC to give the titled compound (8 mg). MS 429.0 and
431.0 (M+H, Cl pattern).
Example 30
5-chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide (41)
[0364] ##STR75##
[0365] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (150 mg, 0.34 mmol), 3-methoxy-2-hydroxypyridine (85 mg,
0.68 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol) and
K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO (2 mL) was degassed
with Ar before being charged with CuI (25 mg, 0.13 mmol). The
mixture in a sealed tube was heated at 130.degree. C. for 4 h. The
mixture was then purified by HPLC to give the titled compound (99
mg). MS 441.0 and 443.0 (M+H, Cl pattern)
Example 31
5-chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide (42)
[0366] ##STR76##
[0367] To a solution of
5-chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide (75 mg, 0.14 mmol) in
CH.sub.2Cl.sub.2 (4 mL), BBr.sub.3 (0.365 mL, 3.8 mmol) was added.
The mixture was stirred at room temperature for 1 h. It was
concentrated in vacuo. The residue was purified by HPLC to give the
titled compound (40 mg). MS 427.0 and 429.0 (M+H, Cl pattern).
Example 32
5-chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (43)
[0368] ##STR77##
[0369] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (66 mg, 0.15 mmol), 3-fluoro-2-hydroxypyridine (46 mg,
0.40 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with
Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture
in a sealed tube was heated at 130.degree. C. overnight. The
mixture was then purified by HPLC to give the titled compound (8
mg). MS 429.0 and 431.0 (M+H, Cl pattern).
Example 33
5-chloro-N-((1-(4-(3-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (44)
[0370] ##STR78##
[0371] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (66 mg, 0.15 mmol), 2-hydroxy-3-methylpyridine (45 mg,
0.41 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with
Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture
in a sealed tube was heated at 130.degree. C. overnight. The
mixture was then purified by HPLC to give the titled compound (10
mg). MS 425.0 and 427.0 (M+H, Cl pattern).
Example 34
5-chloro-N-((1-(4-(5-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (45)
[0372] ##STR79##
[0373] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (56 mg, 0.13 mmol), 2-hydroxy-5-methylpyridine (45 mg,
0.41 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with
Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture
in a sealed tube was heated at 130.degree. C. overnight. The
mixture was then purified by HPLC to give the titled compound (8
mg). MS 425.0 and 427.0 (M+H, Cl pattern).
Example 35
5-chloro-N-((1-(4-(4-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide (46)
[0374] ##STR80##
[0375] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (66 mg, 0.15 mmol), 2,4-dihydroxypyridine (45 mg, 0.41
mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K.sub.2CO.sub.3
(50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being
charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube
was heated at 130.degree. C. overnight. The mixture was then
purified by HPLC to give the titled compound (6 mg). MS 427.0 and
429.0 (M+H, Cl pattern).
Example 36
5-chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-imid-
azol-4-yl)methyl)thiophene-2-carboxamide (47)
[0376] ##STR81##
[0377] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (66 mg, 0.15 mmol), uracil (46 mg, 0.41 mmol),
8-hydroxyquinoline (10 mg, 0.069 mmol) and K.sub.2CO.sub.3 (50 mg,
0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged
with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. The mixture was then purified
by HPLC to give the titled compound (25 mg). MS 428.0 and 430.0
(M+H, Cl pattern).
Example 37
N-((1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-
-5-chlorothiophene-2-carboxamide (48)
[0378] ##STR82##
[0379] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (66 mg, 0.15 mmol), cytosine (46 mg, 0.41 mmol),
8-hydroxyquinoline (10 mg, 0.069 mmol) and K.sub.2CO.sub.3 (50 mg,
0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged
with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. The mixture was then purified
by HPLC to give the titled compound (10 mg). MS 427.1 and 429.1
(M+H, Cl pattern).
Example 38
5-chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl-
)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (49)
[0380] ##STR83##
[0381] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (66 mg, 0.15 mmol), 3-methyluracil (60 mg, 0.48 mmol),
8-hydroxyquinoline (10 mg, 0.069 mmol) and K.sub.2CO.sub.3 (60 mg,
0.43 mmol) in DMSO (1 mL) was degassed with Ar before being charged
with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. The mixture was then purified
by HPLC to give the titled compound (15 mg). MS 442.2 and 444.2
(M+H, Cl pattern).
Example 39
N-((1-(4-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)-5-chlorothiophene-2-carboxamide (50)
[0382] ##STR84##
[0383] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (80 mg, 0.18 mmol), 5-fluorocytosine (60 mg, 0.46 mmol),
8-hydroxyquinoline (12 mg, 0.083 mmol) and K.sub.2CO.sub.3 (60 mg,
0.43 mmol) in DMSO (2 mL) was degassed with Ar before being charged
with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. The mixture was then purified
by HPLC to give the titled compound (15 mg). MS 445.2 and 447.2
(M+H, Cl pattern).
Example 40
N-((1-(4-(4-acetamido-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)met-
hyl)-5-chlorothiophene-2-carboxamide (51)
[0384] ##STR85##
[0385] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (80 mg, 0.18 mmol), N4-acetylcytosine (65 mg, 0.42 mmol),
8-hydroxyquinoline (12 mg, 0.083 mmol) and K.sub.2CO.sub.3 (60 mg,
0.43 mmol) in DMSO (2 mL) was degassed with Ar before being charged
with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was
heated at 130.degree. C. overnight. The mixture was then purified
by HPLC to give the titled compound (3 mg). MS 469.3 and 471.2
(M+H, Cl pattern).
Example 41
5-chloro-N-((1-(4-(2-oxopiperidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thi-
ophene-2-carboxamide (52)
[0386] ##STR86##
[0387] A mixture of
1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
hydrochloride (60 mg, 0.20 mmol) and Pd--C (10%, 31 mg) in MeOH (6
mL) was hydrogenated under balloon H.sub.2 overnight. It was then
filtered through celite. The filtrate was concentrated in vacuo to
give 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one
(54 mg).
[0388] To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5
(43 mg, 0.26 mmol) and triethylamine (0.200 mL, 1.43 mmol) in DMF
(2 mL), BOP (130 mg, 0.29 mmol) was added. After 5 min of stirring,
the solution was added to a solid sample of
1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one (54
mg, 0.18 mmol) in a flask. After being stirred at room temperature
for 2 h, the mixture was purified by HPLC to give the titled
compound (45 mg). MS 415.1 and 417.1 (M+H, Cl pattern).
Example 42
5-chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(piperidin-1-yl)ethoxy)phen-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (53)
[0389] ##STR87##
[0390] A mixture of 2-fluoro-4-iodoaniline (3.00 g, 12.6 mmol),
2-hydroxypyridine 1-7 (1.20 g, 12.6 mmol), 8-hydroxyquinoline
(0.184 g, 1.26 mmol) and K.sub.2CO.sub.3 (3.49 g, 25.3 mmol) in
DMSO (20 mL) was degassed with Ar before being charged with CuI
(0.241 g, 1.27 mmol). The mixture in a sealed tube was heated at
130.degree. C. overnight. After being cooled down to room
temperature, H.sub.2O and nBuOH were added. The organic phase was
separated, concentrated in vacuo to give
1-(4-amino-3-fluorophenyl)pyridin-2(1H)-one as a solid (2.31
g).
[0391] To a solution of trifluoroacetic anhydride (10 mL, 71 mmol)
in CH.sub.2Cl.sub.2 (25 mL) cooled at 0.degree. C., H.sub.2O.sub.2
(50% aq., 4.4 mL, 72 mmol) was added dropwise. After stirring at
0.degree. C. for 1 h, the sample of
1-(4-amino-3-fluorophenyl)pyridin-2(1H)-one (2.31 g, 11.3 mmol) was
added in solid form portion by portion. After addition, the mixture
was gradually removed from 0.degree. C. to room temperature, and it
was stirred at room temperature overnight. The solvent was removed
in vacuo. To the residue, H.sub.2O was added to induce
precipitation, which was collected and dried on vacuum to give
1-(3-fluoro-4-nitrophenyl)pyridin-2(1H)-one (1.37 g).
[0392] To a suspension of
1-(3-fluoro-4-nitrophenyl)pyridin-2(1H)-one (0.70 g, 2.99 mmol) in
anhydrous THF (6 mL) at room temperature, a pre-mixed solution of
1-piperidineethanol (0.40 mL, 3.02 mmol) and NaH (60%, 157 mg, 3.92
mmol) in anhydrous THF (8 mL) was added. After addition, the
suspension became clear. The mixture was stirred at room
temperature overnight. HPLC showed that the reaction was
incomplete. Another pre-mixed solution of 1-piperidineethanol (0.40
mL, 3.02 mmol) and NaH (60%, 157 mg, 3.92 mmol) in anhydrous THF (5
mL) was added. After 1 h of stirring, the reaction was completed.
H.sub.2O and EtOAc were added. The organic phase was separated,
washed with 5% NaHCO.sub.3, dried over Na.sub.2SO.sub.4,
concentrated in vacuo to give
1-(4-nitro-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one
(0.74 g).
[0393] A mixture of
1-(4-nitro-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one
(0.37 g, 1.08 mmol) and Pd--C (10%, 65 mg) in MeOH (15 mL)
containing 6N HCl (0.5 mL) was hydrogenated on a Parr shaker under
45 psi of H.sub.2 overnight. It was then filtered through celite.
The filtrate was concentrated in vacuo to five
1-(4-amino-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one
(0.44 g).
[0394] To a solution of
1-(4-amino-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one
(0.44 g, 1.08 mmol) in conc. HCl (3 mL) at 0.degree. C., a solution
of NaNO.sub.2 (75 mg, 1.08 mmol) in H.sub.2O (2 mL) was added
dropwise. After 30 min of stirring at 0.degree. C., NaI (0.76 g,
5.07 mmol) in H.sub.2O (2 mL) was added. After being stirred at
0.degree. C. for 30 min, the mixture was removed to room
temperature and was stirred at room temperature for 4 h. The
solution was basified with 5 N NaOH to pH 10-12. The product was
extracted with EtOAc, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified
by HPLC to give
1-(4-iodo-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (116
mg).
[0395] A mixture of
1-(4-iodo-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (116
mg, 0.22 mmol),
N-((1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide 3-1
(85 mg, 0.24 mmol), 8-hydroxyquinoline (14 mg, 0.10 mmol) and
K.sub.2CO.sub.3 (200 mg, 1.45 mmol) in DMSO (3 mL) was degassed
with Ar before being charged with CuI (19 mg, 0.10 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give the titled compound (10 mg). MS
538.2 and 540.2 (M+H, Cl pattern).
Example 43
N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indole-
-5-carboxamide (54)
[0396] ##STR88##
[0397] To a solution of indole-5-carboxylic acid (40 mg, 0.25 mmol)
and triethylamine (0.150 mL, 1.08 mmol) in DMF (2 mL), BOP (135 mg,
0.30 mmol) was added. After 5 min of stirring,
1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
hydrochloride (53 mg, 0.18 mmol) was added. The mixture was stirred
at room temperature overnight. It was then purified by HPLC to give
the titled compound (30 mg). MS 410.2 (M+H).
Example 44
5-chloro-N-((2-(methylthio)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazo-
l-4-yl)methyl)thiophene-2-carboxamide (55)
[0398] ##STR89##
[0399] To a suspension of ethyl
2-mercapto-1H-imidazole-4-carboxylate (4.00 g, 23.3 mmol) in
acetone (30 mL) at room temperature, MeI (6 mL, 96.3 mmol) was
added. During first 10 min of stirring, the suspension became
clear, then it turned cloudy as product began to precipitate out.
After being stirred at room temperature overnight, the precipitate
was collected, dried on vacuum to give ethyl
2-(methylthio)-1H-imidazole-4-carboxylate (3.47 g).
[0400] A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol),
ethyl 2-(methylthio)-1H-imidazole-4-carboxylate (2.26 g, 12.1
mmol), 8-hydroxyquinoline (270 mg, 1.86 mmol) and K.sub.2CO.sub.3
(3.40 g, 24.6 mmol) in DMSO (12 mL) was degassed with Ar before
being charged with CuI (345 mg, 1.82 mmol). The mixture in a sealed
tube was heated at 130.degree. C. for 3 days. After cooling down,
H.sub.2O and EtOAc were added. After being filtered through celite,
the organic phase was separated, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was purified by a silica gel
column, eluted with EtOAc in hexane (10-35% EtOAc) to give ethyl
1-(4-iodophenyl)-2-(methylthio)-1H-imidazole-4-carboxylate (0.49
g).
[0401] To a solution of ethyl
1-(4-iodophenyl)-2-(methylthio)-1H-imidazole-4-carboxylate (0.49 g,
1.26 mmol) in anhydrous THF (10 mL) at room temperature, LiBH.sub.4
(2M in THF, 3.2 mL, 6.4 mmol) was added. The mixture was stirred at
room temperature overnight. H.sub.2O and EtOAc were added. The
organic phase was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give
(1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanol (0.41
g).
[0402] To a solution of
(1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanol (0.41 g,
1.18 mmol) in anhydrous dioxane (10 mL), diphenylphosphoryl azide
(0.80 mL, 3.71 mmol) and DBU (0.600 mL, 4.02 mmol) were added. The
mixture in a sealed tube was heated at 110.degree. C. for 3 h.
After being cooled down, H.sub.2O and EtOAc were added. The organic
phase was separated, washed with 5% NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified
by a silica gel column, eluted with EtOAc in hexane (0-20% EtOAc)
to give
4-(azidomethyl)-1-(4-iodophenyl)-2-(methylthio)-1H-imidazole (0.39
g).
[0403] To a solution of
4-(azidomethyl)-1-(4-iodophenyl)-2-(methylthio)-1H-imidazole (0.26
g, 0.70 mmol) in EtOAc (10 mL), Tin(II) chloride dihydrate (0.63 g,
2.8 mmol) was added. The mixture was heated at reflux for 10 min.
After being cooled down, 1 N NaOH (10 mL) was added. The white
precipitate was filtered off through celite. The EtOAc phase was
separated, dried over Na.sub.2SO.sub.4, concentrated in vacuo to
give (1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanamine
(127 mg).
[0404] To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5
(72 mg, 0.44 mmol) and triethylamine (0.150 mL, 1.10 mmol) in DMF
(5 mL), BOP (235 mg, 0.53 mmol) was added. After 5 min of stirring,
the solution was added to the sample of
(1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanamine (127
mg, 0.37 mmol) in a flask. After being stirred at room temperature
overnight, H.sub.2O and EtOAc were added. The organic phase was
separated, washed with 5% NaHCO.sub.3, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was dissolved in CH.sub.3CN (8
mL), H.sub.2O (10 mL) was added to induce precipitation, which was
collected and dried on vacuum to give
5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl-
)thiophene-2-carboxamide (56 mg).
[0405] A mixture of
5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thio-
phene-2-carboxamide (56 mg, 0.11 mmol), 2-hydroxypyridine (30 mg,
0.32 mmol), 8-hydroxyquinoline (8 mg, 0.055 mmol) and
K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed
with Ar before being charged with CuI (15 mg, 0.079 mmol). The
mixture in a sealed tube was heated at 130.degree. C. overnight. It
was then purified by HPLC to give the titled compound (22 mg). MS
457.0 and 459.0 (M+H, Cl pattern).
Example 45
5-chloro-N-((2-(methylsulfonyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imi-
dazol-4-yl)methyl)thiophene-2-carboxamide (56) and
5-chloro-N-((2-(methylsulfinyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide (57)
[0406] ##STR90##
[0407] To a solution of
5-chloro-N-((2-(methylthio)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidaz-
ol-4-yl)methyl)thiophene-2-carboxamide (42 mg, 0.092 mmol) in DMF
(3 mL), a solution of oxone (155 mg, 0.50 mmol) in H.sub.2O (2 mL)
was added. The mixture was stirred at room temperature overnight.
It was then purified by HPLC to give both the sulfone (6 mg) and
sulfoxide (5 mg) products. MS 489.0 and 491.0 (M+H, Cl pattern, for
sulfone); 473.0 and 475.0 (M+H, Cl pattern, for sulfoxide).
Example 46
5-chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide (58)
[0408] ##STR91##
[0409] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (80 mg, 0.18 mmol), pyrazine-2,3-diol (50 mg, 0.44 mmol),
8-hydroxyquinoline (12 mg, 0.083 mmol) and K.sub.2CO.sub.3 (100 mg,
0.72 mmol) in DMSO (1 mL) was degassed with Ar before being charged
with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was
heated at 130.degree. C. for 4 h. The mixture was then purified by
HPLC to give the titled compound (5 mg). MS 428.0 and 430.0 (M+H,
Cl pattern).
Example 47
5-chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-im-
idazol-4-yl)methyl)thiophene-2-carboxamide (59)
[0410] ##STR92##
[0411] A mixture of
5-chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide (30 mg, 0.070 mmol),
2-bromoethanol (0.020 mL, 0.28 mmol) and Cs.sub.2CO.sub.3 (90 mg,
0.28 mmol) in DMSO (1 mL) was stirred at 60.degree. C. for 1 h. It
was then purified by HPLC to give the titled compound (5 mg). MS
471.0 and 473.0 (M+H, Cl pattern).
Example 48
5-chloro-N-((1-(4-(4-ethyl-2,3-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4-y-
l)methyl)thiophene-2-carboxamide (60)
[0412] ##STR93##
[0413] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (70 mg, 0.16 mmol), N-ethylpiperazine-2,3-dione (45 mg,
0.32 mmol), N,N'-dimethylethylenediamine (0.020 mL, 0.19 mmol) and
K.sub.2CO.sub.3 (65 mg, 0.47 mmol) in DMSO (1 mL) and dioxane (1
mL) was degassed with Ar before being charged with CuI (20 mg, 0.10
mmol). The mixture in a sealed tube was heated at 110.degree. C.
overnight. The mixture was then purified by HPLC to give the titled
compound (10 mg). MS 458.1 and 460.1(M+H, Cl pattern).
Example 49
N-((1-(4-(2-(carbamoylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)meth-
yl)-5-chlorothiophene-2-carboxamide (61)
[0414] ##STR94##
[0415] A solution of
(E)-5-chloro-N-((1-(4-(2-cyanamidopyridin-1(2H)-yl)phenyl)-1H-imidazol-4--
yl)methyl)thiophene-2-carboxamide (5 mg, 0.011 mmol) in TFA (0.30
mL) and H.sub.2O (0.030 mL) was stirred at room temperature for 4
h. The solvents were removed in vacuo. The residue was purified by
HPLC to give the titled compound (2 mg). MS 453.0 and 455.1 (M+H,
Cl pattern).
Example 50
5-Chloro-N-((2-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (62)
[0416] ##STR95## ##STR96## Step 1:
[0417] The mixture of 1,4-diiodobenzene 1-1 (600 mg, 1.8 mmol),
2-methyl-1H-imidazole-4-carbaldehyde (200 mg, 1.8 mmol),
K.sub.2CO.sub.3 (503 mg, 3.6 mmol), CuI (105 mg, 0.55 mmol) and
8-hydroxyquinoline (80 mg, 0.55 mol) in 5 mL DMSO and 5 mL dioxane
in a sealed tube was stirred for 2 days at 120.degree. C. It was
cooled to rt, and to it was added 60 mL water. The mixture was
stirred for 30 min and filtered through a celite layer. The
filtrate was concentrated in vacuo and subjected to reverse phase
preparative HPLC to isolate
1-(4-iodophenyl)-2-methyl-1H-imidazole-4-carbaldehyde 5-1. MS found
for C.sub.11HgIN.sub.2O (M+H)+ 313.0.
Step 2:
[0418] The compound prepared in above step (140 mg, 0.45 mmol) was
dissolved in 5 mL methanol and stirred at rt. To it was added
NaBH.sub.4 (26 mg, 0.67 mmol). The mixture was stirred for 30 min
and subjected to preparative HPLC to isolate
(1-(4-iodophenyl)-2-methyl-1H-imidazol-4-yl)methanol 5-2. MS found
for C.sub.11H.sub.11IN.sub.2O (M+H)+ 315.0.
Step 3:
[0419] The compound prepared in above step (126 mg, 0.40 mmol) was
dissolved in 4 mL dry acetonitrile. To it was added 2 mL thionyl
chloride. The mixture was stirred for 40 min and concentrated in
vacuo. The dry residue was then dissolved in 4 mL dry DMF. To it
was added sodium azide (>5 eq). The mixture was stirred at rt
for 1 hr and diluted with EtOAc. It was washed with brine four
times, dried and concentrated in vacuo to give crude
4-(azidomethyl)-1-(4-iodophenyl)-2-methyl-1H-imidazole 5-3. MS
found for C.sub.11H.sub.10IN.sub.5 (M+H)+ 340.0.
Step 4:
[0420] The above prepared crude compound was dissolved in 2 mL
ethanol and 2 mL acetic acid. Iron powder (10 eq) was added in. The
mixture was stirred in 90.degree. C. bath for 30 min. It was
diluted with 20 mL water. The mixture was well stirred and filtered
thru a celite layer. The filtrate was concentrated in vacuo and
subjected to preparative HPLC to isolate
(1-(4-iodophenyl)-2-methyl-1H-imidazol-4-yl)methanamine 5-4. MS
found for C.sub.11H.sub.12IN.sub.3 (M+H)+ 314.0.
Step 5:
[0421] The above prepared compound was dissolved in 50 mL methanol
and treated with MP-carbonate (10 eq). The mixture was gently
stirred for 1 hr and filtered. The filtrate was concentrated in
vacuo to give the corresponding free amine (40 mg, 0.13 mmol). It
was dissolved in 2 mL DMF. To it was added DIEA (16 .mu.L, 0.15
mmol) and stirred at RT. In the meantime,
5-chlorothiophene-2-carboxylic acid 1-5 (24 mg, 0.15 mmol) was
dissolved in 2 mL dry DMF. To it was added DIEA (16 .mu.L, 0.15
mmol) and HATU (57 mg, 0.15 mmol). The mixture was stirred for 10
min. It was added to the stirred solution of the free amine in DMF.
The mixture was stirred for 20 min and subjected to preparative
HPLC to isolate
5-chloro-N-((1-(4-iodophenyl)-2-methyl-1H-imidazol-4-yl)methyl)thiophene--
2-carboxamide 5-5. MS found for C.sub.16H.sub.13CIIN.sub.3OS (M+H)+
458.0, 460.0.
Step 6:
[0422] The above prepared compound (30 mg, 0.07 mmol) was dissolved
in 2 mL DMSO in a sealed tube. To it were added 2-hydroxypyridine
1-7 (20 mg, 0.21 mmol), potassium carbonate (48 mg, 0.35 mmol), CuI
(8 mg, 0.04 mmol) and 8-hydroxyquinoline (6 mg, 0.04 mmol). The
mixture was stirred in 130.degree. C. bath for overnight. The
mixture was filtered and subjected to reverse phase preparative
HPLC to isolate the title compound. MS found for
C.sub.21H.sub.17ClN.sub.4O.sub.2S (M+H)+ 425.1, 427.1.
Example 51
5-Chloro-N-((5-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (63)
[0423] ##STR97## ##STR98## Step 1:
[0424] 1-(4-Iodophenyl)pyridin-2(1H)-one 6-1 (200 mg, 0.67 mmol)
was dissolved in 4 mL DMSO in a sealed tube. To it were added
5-methyl-1H-imidazole-4-carbaldehyde (300 mg, 2.7 mmol),
K.sub.2CO.sub.3 (470 mg, 3.4 mmol), CuI (65 mg, 0.34 mmol) and
8-hydroxyquinoline (50 mg, 0.34 mol). The mixture was stirred at
130.degree. C. for 16 hrs. The mixture was diluted with 100 mL
acetonitrile, well stirred, and filtered through a celite layer.
The filtrate was concentrated and subjected to prep HPLC to isolate
5-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazole-4-carbaldehyde
6-2. MS found for C.sub.16H.sub.13N.sub.3O.sub.2 (M+H)+ 280.1.
Step 2:
[0425] The above prepared compound (120 mg, 0.43 mmol) was stirred
in 10 mL methanol at RT. NaBH.sub.4 (25 mg, 0.64 mmol) was added.
The mixture was stirred for 1 hr and subjected to prep HPLC to
isolate
1-(4-(4-(hydroxymethyl)-5-methyl-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-on-
e 6-3. MS found for C.sub.16H.sub.15N.sub.3O.sub.2 (M+H)+
283.1.
Step 3:
[0426] The above prepared compound (80 mg, 0.28 mmol) was stirred
in 4 mL acetonitrile and 4 mL thionyl chloride. The mixture was
stirred for 1 hr and concentrated in vacuo. The dry residue was
then dissolved in 3 mL DMSO. To it was added sodium azide (10 eq).
The mixture was stirred for 10 min and subjected to prep HPLC to
isolate
1-(4-(4-(azidomethyl)-5-methyl-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
6-4. MS found for C.sub.16H.sub.14N.sub.6O (M+H)+ 307.1.
Step 4:
[0427] The above prepared compound (48 mg, 0.16 mmol) was dissolved
in 1.5 mL ethanol and 3 mL acetic acid. To it was added iron powder
(45 mg, 0.80 mmol). The mixture was stirred at 80.degree. C. for 20
min and diluted with water. It was filtered and subjected to prep
HPLC to isolate
1-(4-(4-(aminomethyl)-5-methyl-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one
6-5. MS found for C.sub.16H.sub.16N.sub.4O (M+H)+ 281.1.
Step 5:
[0428] The above prepared compound was dissolved in 30 mL methanol
and treated with MP-carbonate (10 eq). The mixture was gently
stirred for 1 hr and filtered. The filtrate was concentrated in
vacuo to give the corresponding free amine (45 mg, 0.16 mmol). It
was dissolved in 3 mL DMF. To it was added DIEA (36 .mu.L, 0.20
mmol) and stirred at RT. In the meantime,
5-chlorothiophene-2-carboxylic acid 1-5 (32 mg, 0.20 mmol) was
dissolved in 3 mL dry DMF. To it was added DIEA (36 .mu.L, 0.20
mmol) and HATU (76 mg, 0.20 mmol). The mixture was stirred for 10
min. It was added to the stirred solution of the free amine in DMF.
The mixture was stirred for 1 hr and subjected to preparative HPLC
to isolate the title compound. MS found for
C.sub.21H.sub.17ClN.sub.4O.sub.2S (M+H)+ 425.1, 427.1.
Example 52
5-chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfiny-
l)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (64) and
5-chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfon-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (65)
[0429] ##STR99##
[0430] A mixture of
5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thio-
phene-2-carboxamide (50 mg, 0.10 mmol), 5-fluoro-2-hydroxypyridine
(30 mg, 0.26 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (70 mg, 0.50 mmol) in DMSO (2 mL) was degassed with
Ar before being charged with CuI (14 mg, 0.073 mmol). The mixture
in a sealed tube was heated at 130.degree. C. overnight. After
being cooled down to room temperature, H.sub.2O (5 mL) was added to
induce precipitation, which was collected and dried on vacuum to
give a solid (38 mg).
[0431] To a solution of the solid (38 mg, 0.080 mmol) in DMF (3
mL), a solution of oxone (145 mg, 0.47 mmol) in H.sub.2O (2 mL) was
added. The mixture was stirred at room temperature overnight. It
was then purified by HPLC to give both the sulfone (5 mg) and
sulfoxide (4 mg) products. MS 507.0 and 509.0 (M+H, Cl pattern, for
sulfone); 491.0 and 493.0 (M+H, Cl pattern, for sulfoxide).
Example 53
5-chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfiny-
l)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (66) and
5-chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfon-
yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (67)
[0432] ##STR100##
[0433] A mixture of
5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thio-
phene-2-carboxamide (50 mg, 0.10 mmol), 3-fluoro-2-hydroxypyridine
(30 mg, 0.26 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (70 mg, 0.50 mmol) in DMSO (2 mL) was degassed with
Ar before being charged with CuI (28 mg, 0.15 mmol). The mixture in
a sealed tube was heated at 130.degree. C. overnight. After being
cooled down to room temperature, H.sub.2O (5 mL) was added to
induce precipitation, which was collected and dried on vacuum to
give a solid (34 mg).
[0434] To a solution of the solid (34 mg, 0.072 mmol) in DMF (4
mL), a solution of oxone (200 mg, 0.65 mmol) in H.sub.2O (3 mL) was
added. The mixture was stirred at room temperature overnight. It
was then purified by HPLC to give both the sulfone (2 mg) and
sulfoxide (4 mg) products. MS 507.0 and 509.0 (M+H, Cl pattern, for
sulfone); 491.0 and 493.0 (M+H, Cl pattern, for sulfoxide).
Example 54
5-chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl-
)methyl)thiophene-2-carboxamide (68)
[0435] ##STR101##
[0436] A mixture of
5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxa-
mide 1-6 (66 mg, 0.15 mmol), 5-fluoro-2-hydroxypyridine (46 mg,
0.40 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and
K.sub.2CO.sub.3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with
Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture
in a sealed tube was heated at 130.degree. C. overnight. The
mixture was then purified by HPLC to give the titled compound (6
mg). MS 429.0 and 431.0 (M+H, Cl pattern).
[0437] The compounds in the following Table 1 may be prepared using
methods similar to those above. TABLE-US-00001 TABLE 1 No.
Structure Name 69 ##STR102## 5-chloro-N-((1-(2-(2-
methoxyethoxy)-4-(2- oxopyridin-1(2H)- yl)phenyl)-1H-imidazol-4-
yl)methyl)thiophene-2- carboxamide 70 ##STR103##
(R)-5-chloro-N-((1-(2- (2,3-dihydroxypropoxy)-4-
(2-oxopyridin-1(2H)- yl)phenyl)-1H-imidazol-4-
yl)methyl)thiophene-2- carboxamide 71 ##STR104##
(S)-5-chloro-N-((1-(2-(2,3- dihydroxypropoxy)-4-(2-
oxopyridin-1(2H)- yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2-
carboxamide 72 ##STR105## 5-chloro-N-((1-(2-(2-
hydroxypyridin-4-yl)-4-(2- oxopyridin-1(2H)-
yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 73
##STR106## 5-chloro-N-((1-(2-(6- hydroxypyridin-3-yl)-4-(2-
oxopyridin-1(2H)- yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2-
carboxamide 74 ##STR107## N-((1-(2-(6-aminopyridin-
3-yl)-4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-
imidazol-4-yl)methyl)-5- chlorothiophene-2- carboxamide 75
##STR108## 5-chloro-N-((1-(4-(4- fluoro-2-oxopyridin-1(2H)-
yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 76
##STR109## 5-chloro-N-((1-(4-(6- fluoro-2-oxopyridin-1(2H)-
yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 77
##STR110## 5-chloro-N-((1-(4-(5- hydroxy-2-oxopyridin-
1(2H)-yl)phenyl)-1H- imidazol-4- yl)methyl)thiophene-2- carboxamide
78 ##STR111## 5-chloro-N-((1-(4-(6- hydroxy-2-oxopyridin-
1(2H)-yl)phenyl)-1H- imidazol-4- yl)methyl)thiophene-2-
carboxamide
Example 55
[0438] This example illustrates methods for evaluating the
compounds of the invention, along with results obtained for such
assays. The in vitro and in vivo human Factor Xa activities of the
inventive compounds can be determined by various procedures known
in the art, such as a test for their ability to inhibit the
activity of human plasma Factor Xa. The potent affinities for human
Factor Xa inhibition exhibited by the inventive compounds can be
measured by an IC.sub.50 value (in nM). The IC.sub.50 value is the
concentration (in nM) of the compound required to provide 50%
inhibition of human Factor Xa proteolytic activity. The smaller the
IC.sub.50 value, the more active (potent) is a compound for
inhibiting Factor Xa activity.
[0439] An in vitro assay for detecting and measuring inhibition
activity against Factor Xa is as follows:
IC.sub.50 and Ki Determinations:
Substrate:
[0440] The substrate S-2765 (Z-D-Arg-Gly-Arg-pNA.HCl) was obtained
from Diapharma (West Chester, Ohio).
Enzyme:
[0441] The human plasma protein factor Xa was purchased from
Haematologic Technologies (Essex Junction, Vt.).
Methods:
[0442] IC.sub.50 Determinations
[0443] All assays, which are performed in 96-well microtiter
plates, measure proteolytic activity of the enzyme (factor Xa) by
following cleavage of a paranitroanilide peptide substrate. The
assay buffer used for proteolytic assays was Tris buffered saline
(20 mM Tris, 150 mM NaCl, 5 mM CaCl.sub.2, 0.1% Bovine serum
albumin (BSA), 5% Dimethly Sulfoxide (DMSO) pH 7.4). In a 96-well
microtiter plate, inhibitor was serially diluted to give a range of
final concentrations from 0.01 nM to 10 .mu.M. Duplicate sets of
wells were assayed and control wells without inhibitor were
included. Enzyme was added to each well, (factor Xa concentration=1
nM), the plate was shaken for 5 seconds and then incubated for 5
minutes at room temperature. S2765 was added (100 .mu.M final) and
the plate was shaken for 5 seconds (final volume in each well was
200 .mu.l). The degree of substrate hydrolysis was measured at 405
nm on a Thermomax plate reader (Molecular Devices, Sunnyvale,
Calif.) for 2 minutes. The initial velocities of substrate cleavage
(mOD/min), for each range of inhibitor concentrations, were fitted
to a four parameter equation using Softmax data analysis software.
The parameter C, derived from the resulting curve-fit, corresponded
to the concentration for half maximal inhibition (IC.sub.50).
[0444] K.sub.i Determination
[0445] The assay buffer for this series of assays was Hepes
buffered saline (20 mM Hepes, 150 mM NaCl, 5 mM CaCl.sub.2, 0.1%
PEG-8000, pH 7.4). In a 96-well microtiter plate, inhibitor was
serially diluted in a duplicate set of wells to give a range of
final concentrations from 5 pM to 3 .mu.M. Controls without
inhibitor (8 wells) were included. The enzyme, factor Xa (final
concentration=1 nM) was added to the wells. The substrate S-2765
(final concentration=200 .mu.M) was added and the degree of
substrate hydrolysis was measured at 405 nm on a Thermomax plate
reader for 5 minutes, using Softmax software. Initial velocities
(mOD/min) were analyzed by non-linear least squares regression in
the Plate K.sub.i software (BioKin Ltd, Pullman, W A) [Kusmic, et
al., Analytical Biochemistry 281: 62-67, 2000]. The model used for
fitting the inhibitor dose-response curves was the Morrison
equation. An apparent K.sub.i (Ki*) was determined. The overall
K.sub.i was calculated using the following equation: Ki = Ki * 1 +
[ S ] Km ##EQU1## where [S] is substrate concentration (200 .mu.M)
and K.sub.m, the Michaelis constant for S2765.
[0446] The following examples exhibited Factor Xa IC.sub.50 values
less than or equal to 100 nM: 10-12, 14, 15, 18, 21-27, 30, 32,
33-36, 39-45, 47-53, 55-59, 61-62, and 64-67.
[0447] The following examples exhibited Factor Xa IC.sub.50 values
greater than 100 nM and less than 500 nM: 17, 19, 28, and 46.
[0448] The following examples exhibited Factor Xa IC.sub.50 values
greater than or equal to 500 nM: 13, 16, 20, 29, 31, 37-38, 54, 60,
and 63.
Example 56
[0449] Compound 10 was used in the rat investigation. An
intravenous (IV) and oral (PO) dose of Compound 10 (1.0 and 10
mg/kg, respectively) was prepared. The IV dose was solubilized in
50% PEG300 to yield a final concentration of 1.0 mg/mL with a final
pH of 5.13. The PO dose was suspended in 0.5% methylcellulose at a
concentration of 2.0 mg/mL with a final pH of 2.70.
[0450] For the dog and monkey study, Compound 10 was also used. An
IV and PO dose of Compound 10 (1.0 and 5.0 mg/kg, respectively) was
prepared. The IV dose was formulated similarly to that used in the
rat study (50% PEG300 in water). The PO dose was suspended in 0.5%
methylcellulose at a concentration of 1.0 mg/mL with a final pH of
approximately 3.50.
Study Design
[0451] A total of six male Sprague-Dawley rats (n=3/dosing group)
from Charles River Laboratories (Hollister, Calif.), three male
beagle dogs from Marshall BioResources (North Rose, N.Y.) and three
male rhesus monkeys were utilized. All surgical procedures in rat
(femoral and jugular vein catheterizations) were performed 8 days
prior to utilization in the study and rats were acclimated in-house
5 days prior to utilization. Dogs were acclimated in-house at least
seven days prior to utilization and were returned to the colony at
the completion of the study. Monkey studies were conducted by an
off-site contract laboratory.
[0452] All animals were fasted from the afternoon prior to study
initiation to two hours post-dose (approximately 18 hours). Water
was provided ad libitum. All animal rooms were on a 12 hour
light-dark cycles (6 A.M. to 6 P.M.). On the morning of
experimentation, animals were weighed. Rat femoral and jugular (IV
only) vein blood lines were exteriorized and attached to access
ports. Dogs were weighed and shaved at blood sampling and IV dosing
sites (along both cephalic and saphenous veins).
[0453] All animals were dosed based on individual weights with a PO
gavage volume of 5.0 mL/kg and an IV bolus dose volume of 1.0
mL/kg. Blood samples were obtained on 3.8% TSC (1:10 dilution) over
a 24, 56, and 96 hour period post-dosing for the rat, dog, and
monkey, respectively. Blood samples were centrifuged for platelet
poor plasma, and resulting plasma was stored at -20.degree. C.
until sample analysis. Rat urine samples were collected on 200
.mu.L of 2% boric acid from animals in the IV group at 0
(overnight), 10, and 24 hours post-dose. At collection times, urine
volume and water consumption was recorded. Urine samples were
stored at -20.degree. C. until sample analysis.
Sample Analysis
[0454] Plasma and urine samples were analyzed for Compound 10
concentration using a liquid chromatography tandem mass
spectrometry (LC/MS/MS). In brief, plasma and urine samples were
processed in a 96-well Captiva.TM. filter plate (0.2 .mu.m, Varian,
Inc., Palo Alto, Calif.). Aliquots of plasma samples were
precipitated with acetonitrile containing 500 ng/mL of
N-(2-(5-chloropyridin-2-ylcarbaomoyl)-4-methoxyphenyl)-4-(N,N-dimethylcar-
bamimidoyl)-2-fluorobenzamide, an internal standard. Aliquots of
urine samples were diluted with plasma before mixing with
acetonitrile containing internal standard. The mixture was vortexed
and refrigerated at 4.degree. C. for 30 minutes to allow complete
protein precipitation. The mixture was filtered into a 96-well
collection plate. The filtrate was injected onto a Sciex API3000
LC/MS/MS equipped with a turbo-ion spray source. Compound 10 and
N-(2-(5-chloropyridin-2-ylcarbaomoyl)-4-methoxyphenyl)-4-(N,N-dimethylcar-
bamimidoyl)-2-fluorobenzamide were separated on a Thermo
Hypersil-Keystone Betasil C.sub.18 column (4.6.times.100 mm, 5
.mu.m; Fisher Scientific, Houston, Tex.). A mobile phase gradient
mixture of 90% mobile phase A (0.5% formic acid in water) and 10%
mobile phase B (0.5% formic acid in 90% acetonitrile) to 40% mobile
phase B (programmed over 2.8 minutes). The peak areas of the m/z
411.fwdarw.250 product ion (Compound 10) were measured against
those of the m/z 470.fwdarw.342 product ion
(N-(2-(5-chloropyridin-2-ylcarbaomoyl)-4-methoxyphenyl)-4-(N,N-dimethylca-
rbamimidoyl)-2-fluorobenzamide) in positive ion mode. The
analytical range was 0.500 to 10,000 ng/mL.
Data Analysis
[0455] Sample Compound 10 concentrations below the lower limit of
quantitation (LLQ) were reported as <0.500 ng/mL. These values
were treated as zero for pharmacokinetic calculations.
[0456] Compound 10 pharmacokinetic parameter values were calculated
by noncompartmental analysis of the plasma concentration-time data
using Watson LIMS software (version 7.1). Terminal elimination rate
constant (k) was calculated as the absolute value of the slope of
linear regression of the natural logarithm (ln) of plasma
concentration versus time during the terminal phase of the plasma
concentration-time profile. Apparent terminal half-life (T.sub.1/2)
values were calculated as ln(2)/k. Area under the plasma
concentration-time profile (AUC) values were estimated using the
linear trapezoidal rule. AUC.sub.all values were calculated from
time 0 to the time of the last detectable concentration.
AUC.sub.(0-inf) values were calculated as the sum of the
corresponding AUC.sub.all and the last detectable concentration
divided by k. Systemic clearance (CL) was calculated from IV
Dose/AUC.sub.(0-inf). Volume of distribution (Vz) was calculated
from IV Dose/[k.cndot.AUC.sub.(0-inf)]. Volume of distribution at
steady-state (Vss) was calculated from CL* Mean Residence Time.
Maximum plasma concentrations (C.sub.max) and time to reach
C.sub.max(T.sub.max) were recorded as observed. Percentage oral
bioavailability was calculated by taking the ratio of
dose-normalized AUC.sub.(0-inf) values (AUC/D) following PO and IV
administration. The results are shown in Tables 2-3 and the Figures
below. TABLE-US-00002 TABLE 2 Pharmacokinetic parameters of
Compound 10 in rat, dog, and monkey after intravenous
administration determined by noncompartmental analysis Mean .+-. SD
Parameter Unit Rat Dog Monkey Dose mg/kg 1 1 1 T.sub.1/2 hr 2.86
.+-. 1.40 AUC.sub.all ng*hr/mL 5376 .+-. 1186 1615 .+-. 360 12550
.+-. 5995 AUC.sub.(0-inf) ng*hr/mL 5404 .+-. 1163 1622 .+-. 363
12560 .+-. 5998 Vz L/kg 0.757 .+-. 0.328 2.73 .+-. 2.45 2.31 .+-.
1.71 CL mL/min/kg 3.19 .+-. 0.734 10.7 .+-. 2.69 1.66 .+-. 1.06 Vss
L/kg 0.368 .+-. 0.026 0.843 .+-. 0.288 0.353 .+-. 0.059 Dose
excreted unchanged % 0.248 .+-. 0.019 in urine Noncompartmental
analysis was performed using Watson LIMS software (version 7.1).
T.sub.1/2: Terminal half-life AUC: Area under the plasma
concentration vs. time curve Vz: Volume of distribution CL:
Systemic clearance Vss: Volume of distribution at steady-state
[0457] TABLE-US-00003 TABLE 3 Pharmacokinetic parameters of
Compound 10 in rat, dog, and monkey after oral administration
determined by noncompartmental analysis Mean .+-. SD Parameter Unit
Rat Dog Monkey Dose mg/kg 10 5 5 T.sub.1/2 hr 2.72 .+-. 0.29
T.sub.max hr 0.250 .+-. 0.00 0.583 .+-. 0.382 2.00 .+-. 0.00
C.sub.max ng/mL 28890.+-. 2084 2717 .+-. 474 6041 .+-. 1877
AUC.sub.all ng*hr/mL 68510 .+-. 12510 5464 .+-. 1471 42140 .+-.
17240 AUC.sub.(0-inf) ng*hr/mL 68590 .+-. 12490 5475 .+-. 1475
42150 .+-. 17250 AUC/D kg*hr/mL 6859 .+-. 1249 1095 .+-. 295 8430
.+-. 3449 F % 127 .+-. 23.1 68.5 .+-. 15.5 71.6 .+-. 18.1
Noncompartmental analysis was performed using Watson LIMS software
(version 7.1). T.sub.1/2: Terminal half-life T.sub.max: Time to
reach maximal plasma concentration C.sub.max: Maximal plasma
concentration AUC: Area under the plasma concentration vs. time
curve % F: Absolute bioavailability
[0458] The present invention provides a number of embodiments. It
is apparent that the examples may be altered to provide other
embodiments of this invention. Therefore, it will be appreciated
that the scope of this invention is to be defined by the appended
claims rather than by the specific embodiments, which have been
represented by way of example.
* * * * *