U.S. patent application number 11/377104 was filed with the patent office on 2006-08-03 for methods of treating factor viia-associated conditions with compounds having an amine nucleus.
Invention is credited to Gregory S. Bisacchi, Timothy Herpin, Zulan Pi, E. Scott Priestley.
Application Number | 20060173057 11/377104 |
Document ID | / |
Family ID | 30000475 |
Filed Date | 2006-08-03 |
United States Patent
Application |
20060173057 |
Kind Code |
A1 |
Herpin; Timothy ; et
al. |
August 3, 2006 |
Methods of treating factor VIIa-associated conditions with
compounds having an amine nucleus
Abstract
Methods of treating Factor VIIa-associated conditions in a
mammal are described, comprising administering to the mammal in
need of treatment thereof an effective amount of at least one
compound having the formula (I), ##STR1## or a
pharmaceutically-acceptable salt, hydrate or prodrug thereof.
Inventors: |
Herpin; Timothy; (Princeton,
NJ) ; Bisacchi; Gregory S.; (Ringoes, NJ) ;
Pi; Zulan; (Pennington, NJ) ; Priestley; E.
Scott; (Yardley, PA) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
30000475 |
Appl. No.: |
11/377104 |
Filed: |
March 16, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10464366 |
Jun 17, 2003 |
7041692 |
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11377104 |
Mar 16, 2006 |
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60389833 |
Jun 19, 2002 |
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Current U.S.
Class: |
514/377 ;
548/233 |
Current CPC
Class: |
C07D 231/12 20130101;
C07D 249/08 20130101; A61K 31/415 20130101; A61K 31/4196 20130101;
A61P 9/08 20180101; C07D 413/12 20130101; A61K 31/4172 20130101;
C07D 413/14 20130101; C07D 417/12 20130101; C07D 233/56 20130101;
A61K 31/421 20130101; A61K 31/422 20130101; C07D 263/48
20130101 |
Class at
Publication: |
514/377 ;
548/233 |
International
Class: |
A61K 31/421 20060101
A61K031/421; C07D 263/48 20060101 C07D263/48; A61K 31/422 20060101
A61K031/422 |
Claims
1. A compound having the formula (II), ##STR90## or a
pharmaceutically-acceptable salt, or hydrate, or prodrug thereof,
wherein A is selected from phenyl, oxazolyl, thiazolyl,
isothiazolyl, imidazolyl, furyl, thienyl, thiadiazolyl,
oxadiazolyl, tetrazolyl, triazolyl, diazolyl, pyrrolyl, and
pyrazolyl, said ring A being optionally substituted with up to two
groups selected from halogen, NO.sub.2, C.sub.1-4alkyl, haloalkyl,
haloalkoxy, OH, C.sub.1-4alkoxy, C.sub.1-4alkylcarbonyl, CN,
NH.sub.2, NH(C.sub.1-4alkyl), and N(alkyl).sub.2; R.sub.3 is
selected from hydrogen, halogen, C.sub.1-4alkyl,
hydroxy(C.sub.0-4alkyl), CF.sub.3(C.sub.0-4alkyl),
OCF.sub.3(C.sub.0-4alkyl), cyano(C.sub.0-4alkyl),
amino(C.sub.0-4alkyl), C.sub.1-3alkoxy(C.sub.0-4alkyl), and
C.sub.1-6alkylamino(C.sub.0-4alkyl); R.sub.11 is selected from
hydrogen, halogen, C.sub.1-4alkyl, hydroxy(C.sub.0-4alkyl),
CF.sub.3(C.sub.0-4alkyl), OCF.sub.3(C.sub.0-4alkyl),
cyano(C.sub.0-4alkyl), amino(C.sub.0-4alkyl),
C.sub.1-3alkoxy(C.sub.0-4alkyl), and
C.sub.1-6alkylamino(C.sub.0-4alkyl), or two R.sub.11 groups may be
taken together, or one of R.sub.11 may be taken together with
R.sub.11a to form a fused benzo, heteroaryl, or heterocyclic ring,
wherein said ring in turn is optionally substituted with a group A
or one to two of C.sub.1-4alkyl, oxo(.dbd.O), halogen, cyano,
trifluoromethyl, or trifluoromethoxy; R.sub.11a is selected from
hydrogen, halogen, C.sub.1-4alkyl, hydroxy(C.sub.0-4alkyl),
CF.sub.3(C.sub.0-4alkyl), OCF.sub.3(C.sub.0-4alkyl),
cyano(C.sub.0-4alkyl), and C.sub.1-4alkoxy(C.sub.0-4alkyl), or
R.sub.11a may be taken together with R.sub.11 to form a fused
benzo, heteroaryl, or heterocyclic ring, wherein said ring in turn
is optionally substituted with a group A or one to two of
C.sub.1-4alkyl, oxo(.dbd.O), halogen, cyano, trifluoromethyl, or
trifluoromethoxy; a is 0 or 1; and n is 0, 1, 2, 3, or 4; and said
compound of formula (II) is effective in inhibiting Factor VIIa in
a mammal with an IC.sub.50 of less than 1 .mu.M.
2. A compound according to claim 1, having the formula, ##STR91##
or a pharmaceutically-acceptable salt, hydrate, or prodrug thereof,
wherein said compound is effective in inhibiting Factor VIIa in a
mammal with an IC.sub.50 of less than 500 nM.
3. A pharmaceutical composition, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 1.
4. A pharmaceutical composition, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 2.
5. A method of treating a disorder selected from myocardial
infarction, unstable angina, thromboembolic stroke, venous
thrombosis, pulmonary embolism, peripheral occlusive arterial
disease, atherosclerotic vascular disease, athersclerotic plaque
rupture, and/or thromboembolic consequences of surgery,
interventional cardiology, and immobility, in a mammal comprising
administering to the mammal in need of treatment thereof an
effective amount of at least one compound of claim 1.
6. A method of treating a disorder selected from myocardial
infarction, unstable angina, thromboembolic stroke, venous
thrombosis, pulmonary embolism, peripheral occlusive arterial
disease, atherosclerotic vascular disease, athersclerotic plaque
rupture, and/or thromboembolic consequences of surgery,
interventional cardiology, and immobility, in a mammal comprising
administering to the mammal in need of treatment thereof an
effective amount of at least one compound of claim 2.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of U.S.
application Ser. No. 10/464,366, filed Jun. 17, 2003, now allowed,
which claims the priority benefit of U.S. Provisional Application
No. 60/389,833, filed Jun. 19, 2002, which is expressly
incorporated fully herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of treating
conditions associated with the activity of Factor VIIa comprising
administration of compounds having an amine nucleus, as further
defined herein. The invention further relates to select compounds
having surprisingly advantageous activity in inhibiting Factor
VIIa.
BACKGROUND OF THE INVENTION
[0003] An elevated blood plasma level of Factor VIIa is a risk
factor for cardiovascular disease and abnormalities of the
coagulation system. Uncontrolled FVIIa activation can lead to
occlusive arterial thrombosis and thromboembolism which can produce
unstable angina, myocardial infarction, and stroke. It is estimated
that this year 1.1 million Americans will have a new or secondary
heart attack, and about one third of them will die. This makes
arterial thrombotic diseases the single leading cause of death in
America. Stroke killed an estimated 158,000 people in 1995 and is
the third largest cause of death (ranking behind heart disease and
all forms of cancer). Stroke is also the single leading cause of
disability in the United States.
[0004] Thrombosis in the veins deep in thighs or calves (deep vein
thrombosis) can lead to ischemia, pain, tenderness, and
discoloration of the affected area. A major complication of venous
thrombosis is pulmonary embolism, i.e., a clot breaks free and
travels through the venous circulation and right heart to the
pulmonary circulation, where it blocks an artery of the lung.
Pulmonary function is compromised and death may follow. It is
estimated that there are about 50,000 deaths per year resulting
from pulmonary embolism (Moser, 1990).
[0005] FVIIa activation can also result from gram-negative
bacteremia which causes half of the cases of lethal septic shock
acquired during hospitalization. Bacterial lipopolysaccharide (LPS)
and inflammatory mediators mediate some of the sequelae including a
coagulopathy that may be triggered by expression of tissue factor
(TF) on macrophages and endothelial cells.
[0006] Accordingly, antithrombotic agents have been researched and
developed for use in treating cardiovascular and other diseases.
Presently, antithrombotic agents include heparin, coumarin, and
aspirin, among others. There are, however, limitations with these
agents. For example, both heparin and coumarin have a
highly-variable dose-related response, and their anticoagulant
effects must be closely monitored to avoid a risk of serious
bleeding. The erratic anticoagulant response of heparin is likely
due to its propensity to bind non-specifically to plasma proteins.
Aspirin has a limited efficacy and at high doses presents a risk of
gastrointestinal bleeding. Thrombin inhibitors and their drawbacks
are further discussed in WO 96/20689 to duPont Merck Pharmaceutical
Co.
[0007] As may be appreciated, those in the field of pharmaceutical
research continue to seek to develop new compounds and compositions
having increased effectiveness and bioavailability and/or having
fewer side effects. There is particularly an interest in developing
agents that can selectively and directly inhibit key factors in the
complicated coagulation process. The present invention provides
compounds useful as inhibitors of Factor VIIa. Amino-based
compounds useful as IMPDH inhibitors are disclosed in U.S. Pat. No.
6,399,773, and compounds useful as IMPDH inhibitors and Factor VIIa
inhibitors are disclosed in U.S. patent application Ser. No.
09/997,963, filed Nov. 29, 2001, a continuation-in-part application
to U.S. patent application Ser. No. 09/428,432. Additionally,
compounds useful in treating Factor VIIa conditions are described
in U.S. provisional application Ser. No. 60/389,832, titled
"Ureido-Substituted Aniline Compounds Useful As Serine Protease
Inhibitors," filed Jun. 19, 2002, with common inventors herein and
assigned to the present assignee. Each of the patents, patent
applications, and articles cited herein are incorporated herein by
reference.
SUMMARY OF THE INVENTION
[0008] The instant invention comprises methods of treating Factor
VIIa-associated conditions in a mammal comprising administering to
the mammal in need of treatment thereof, an effective amount of at
least one compound having the formula (I), ##STR2## or a
pharmaceutically-acceptable salt, hydrate or prodrug thereof,
wherein:
[0009] A is a five or six-membered saturated or unsaturated
carbocyclic, heterocyclic or heteroaryl ring, said ring A being
optionally substituted with up to three groups selected from
R.sub.27;
[0010] B is selected from one of ##STR3##
[0011] D is phenyl, cycloalkyl, or a five to six-membered
heteroaryl or heterocyclo, provided, however, that when A is a
heterocyclo or heteroaryl and a is 1, then D is phenyl or
cycloalkyl;
[0012] R.sub.1 is hydrogen, C.sub.1-4alkyl, or C.sub.1-4alkyl
substituted with one to two R.sub.21;
[0013] R.sub.2 and R.sub.3 are attached to any available carbon
atom of ring B and ring D, respectively, and at each occurrence are
independently selected from halogen, cyano, NO.sub.2,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, haloalkyl, haloalkoxy, --OR.sub.15,
--C(.dbd.O)R.sub.15, --OC(.dbd.O)R.sub.15, --CO.sub.2R.sub.15,
--OCO.sub.2R.sub.15, --C(.dbd.O)NR.sub.15R.sub.16,
--OC(--O)NR.sub.15R.sub.16, --NR.sub.15R.sub.16,
--NR.sub.16C(.dbd.O)R.sub.15,
--NR.sub.16aC(.dbd.O)NR.sub.15R.sub.16,
--NR.sub.16CO.sub.2R.sub.15, --SR.sub.15, --S(O)R.sub.15,
--SO.sub.2R.sub.15, --SO.sub.2NR.sub.15R.sub.16,
--SO.sub.3R.sub.15, --NR.sub.16SO.sub.2R.sub.15, and
--NR.sub.16aSO.sub.2NR.sub.15R.sub.16;
[0014] R.sub.4 and R.sub.5 are independently selected from
hydrogen, halogen, hydroxy, cyano, C.sub.1-3alkoxy, --OCF.sub.3,
CF.sub.3, amino, C.sub.1-6alkylamino, C.sub.1-4alkyl, and
C.sub.1-4alkyl substituted with one to two R.sub.22; or
alternatively, R.sub.4 and R.sub.5 taken together may form a 3-8
membered cycloalkyl or heterocyclic spiro ring, said ring being
optionally substituted with up to three R.sub.28;
[0015] R.sub.6 is hydrogen, C.sub.1-4alkyl, or C.sub.1-4alkyl
substituted with one to two R.sub.23;
[0016] R.sub.7 and R.sub.8 are independently selected from
hydrogen, halogen, hydroxy, cyano, C.sub.1-3alkoxy, --OCF.sub.3,
CF.sub.3, amino, C.sub.1-6alkylamino, C.sub.1-4alkyl, and
C.sub.1-4alkyl substituted with one to two R.sub.24; or
alternatively, R.sub.7 and R.sub.8 taken together may form a 3-8
membered cycloalkyl or heterocyclic spiro ring, said ring being
optionally substituted with up to three R.sub.29; or alternatively,
one or both of R.sub.7 and R.sub.8 may be taken together with one
or both of R.sub.9 and R.sub.10 to form a heterocyclic or
heteroaryl ring, said ring in turn being optionally substituted
with up to three R.sub.30;
[0017] R.sub.9 and R.sub.10 are independently selected from
hydrogen, C.sub.1-4alkyl, and C.sub.1-4alkyl substituted with one
to two R.sub.25; or alternatively, R.sub.9 and R.sub.10 taken
together may form a 3-8 membered heterocyclic ring or a five to six
membered heteroaryl ring, said ring being optionally substituted
with up to three R.sub.30; or alternatively, one or both of R.sub.9
and R.sub.10 may be taken together with one or both of R.sub.7 and
R.sub.8 to form a heterocyclic or heteroaryl ring, said ring being
optionally substituted with up to three R.sub.30;
[0018] R.sub.11 at each occurrence is independently selected from
halogen, cyano, NO.sub.2, C.sub.1-6alkyl, substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, haloalkyl,
haloalkoxy, --OR.sub.13, --C(.dbd.O)R.sub.13, --OC(.dbd.O)R.sub.13,
--CO.sub.2R.sub.13, --OCO.sub.2R.sub.13,
--C(.dbd.O)NR.sub.13R.sub.14, --OC(.dbd.O)NR.sub.13R.sub.14,
--NR.sub.13R.sub.14, --NR.sub.14C(.dbd.O)R.sub.13a,
--NR.sub.14CO.sub.2R.sub.13, --SR.sub.13, --S(O)R.sub.13,
--SO.sub.2R.sub.13, --SO.sub.2NR.sub.13R.sub.14,
--SO.sub.3R.sub.13, --NR.sub.14SO.sub.2R.sub.13, and
--NR.sub.14aSO.sub.2NR.sub.13R.sub.14; or alternatively, two
R.sub.11 groups may be taken together to form a fused benzo,
heteroaryl, or heterocyclic ring, wherein said ring in turn is
optionally substituted with up to one A group and/or one to two
R.sub.31; provided, however, that R.sub.11 is not alkyl substituted
with --NR.sub.18aC(.dbd.O)NR.sub.17R.sub.18;
[0019] R.sub.13, R.sub.14, and R.sub.14a at each occurrence
independently of each other are selected from hydrogen,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.3-10cycloalkyl(C.sub.0-4alkyl),
aryl(C.sub.0-4alkyl), heterocyclo(C.sub.0-4alkyl), and
heteroaryl(C.sub.0-4alkyl), wherein each of said cycloalkyl, aryl,
heterocyclo, and heteroaryl groups are optionally substituted with
up to two substituents independently selected from R.sub.32;
provided, however, that when R.sub.13 is attached to a sulfonyl
group as in --SO.sub.2R.sub.13, --S(.dbd.O)R.sub.13, and
--SO.sub.3R.sub.13, then R.sub.13 is not hydrogen; or
alternatively, R.sub.13 and R.sub.14 can be taken together with the
nitrogen atom to which they are attached to form a heterocyclo or
heteroaryl, said ring being in turn optionally substituted with up
to three groups selected from R.sub.32;
[0020] R.sub.13a is selected from hydrogen, C.sub.1-6alkyl,
substituted C.sub.1-6alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-10cycloalkyl(C.sub.0-4alkyl), aryl(C.sub.0-4alkyl),
heterocyclo(C.sub.1-4alkyl), and heteroaryl(C.sub.1-4alkyl),
wherein each of said cycloalkyl, aryl, heterocyclo, and heteroaryl
groups are optionally substituted with up to two substituents
independently selected from R.sub.32;
[0021] R.sub.15 at each occurrence independently of each other
R.sub.15 is selected from hydrogen, C.sub.1-6alkyl, substituted
C.sub.1-6alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.3-10cycloalkyl(C.sub.0-4alkyl), aryl(C.sub.0-4alkyl),
heterocyclo(C.sub.0-4alkyl), and heteroaryl(C.sub.0-4alkyl),
wherein each of said cycloalkyl, aryl, heterocyclo, and heteroaryl
groups are optionally substituted with up to two substituents
independently selected from R.sub.33; provided, however, that when
R.sub.15 is attached to a sulfonyl group as in --SO.sub.2R.sub.15,
--S(.dbd.O)R.sub.15, and --SO.sub.3R.sub.15, then R.sub.15 is not
hydrogen;
[0022] R.sub.16 and R.sub.16a at each occurrence independently of
each other R.sub.16 and R.sub.16a are selected from hydrogen,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, --OR.sub.19, --C(.dbd.O)R.sub.19,
--CO.sub.2R.sub.19, --SO.sub.2R.sub.19,
C.sub.3-10cycloalkyl(C.sub.0-4alkyl), aryl(C.sub.0-4alkyl),
heterocyclo(C.sub.0-4alkyl), and heteroaryl(C.sub.0-4alkyl),
wherein R.sub.19 is C.sub.1-6alkyl, C.sub.3-10cycloalkyl, aryl,
heterocyclo, or heteroaryl, and each of said R.sub.19, cycloalkyl,
aryl, heterocyclo, and heteroaryl groups are in turn optionally
substituted with up to two substituents independently selected from
R.sub.34;
[0023] alternatively, R.sub.15 and R.sub.16 can be taken together
with the nitrogen atom to which they are attached to form a
heterocyclo or heteroaryl, said ring being in turn optionally
substituted with up to three groups selected from R.sub.34;
[0024] R.sub.17 and R.sub.18 are independently selected from
hydrogen, alkyl, substituted alkyl, cyano, hydroxy, alkoxy,
cycloalkyl, heterocyclo, aryl and heteroaryl, or taken together may
form a heteroaryl or heterocyclo ring;
[0025] R.sub.17a is hydrogen, alkyl, or substituted alkyl;
[0026] R.sub.21, R.sub.22, R.sub.23, R.sub.24, R.sub.25, and
R.sub.26 are independently selected from halogen, cyano, hydroxy,
C.sub.1-3alkoxy, OCF.sub.3, CF.sub.3, amino, and
C.sub.1-6alkylamino;
[0027] R.sub.27, R.sub.28, R.sub.29, R.sub.30, R.sub.31, R.sub.32,
R.sub.33, and R.sub.34 are at each occurrence independently
selected from C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
oxo (.dbd.O), halo(C.sub.0-4alkyl), NO.sub.2(C.sub.0-4alkyl),
hydroxy(C.sub.0-4alkyl), CF.sub.3(C.sub.0-4alkyl),
OCF.sub.3(C.sub.0-4alkyl), cyano(C.sub.0-4alkyl),
amino(C.sub.0-4alkyl), C.sub.1-4alkoxy(C.sub.0-4alkyl),
C.sub.1-6alkylamino(C.sub.0-4alkyl),
C.sub.1-4alkylthio(C.sub.0-4alkyl), carbamyl(C.sub.0-4alkyl),
--C(.dbd.O)C.sub.1-4alkyl, --CO.sub.2C.sub.1-4alkyl,
--S(O)(C.sub.1-4alkyl), --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4alkyl), --SO.sub.3H,
--SO.sub.3(C.sub.1-4alkyl), --NHCO(C.sub.1-6alkyl), and
--C(.dbd.O)NH(C.sub.1-4alkyl), provided, however, that when
R.sub.26, R.sub.27, R.sub.30, R.sub.31, R.sub.32, R.sub.33, and
R.sub.34 are substituents attached to an aryl or heteroaryl ring,
said groups are not selected from oxo (.dbd.O); provided further,
that when R.sub.26, R.sub.27, R.sub.30, R.sub.31, R.sub.32,
R.sub.33, and R.sub.34 are hydroxy and attached to an aryl or
heteroaryl ring, the ring may undergo tautomerization to an oxo
species, or exist as an equilibrium mixture of both tautomers;
[0028] a is 0 or 1;
[0029] m is 0, 1, or 2;
[0030] n is 0, 1, 2, 3, or 4;
[0031] p is 0, 1 or 2; and
[0032] q is 0, 1, 2, 3 or 4.
[0033] Also included within the scope of the present invention are
select compounds having surprisingly advantageous activity in
inhibiting Factor VIIa.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The following are definitions of terms used in this
specification. The initial definition provided for a group or term
herein applies to that group or term throughout this specification,
individually or as part of another group, unless otherwise
indicated.
[0035] The term "alkyl" refers to straight or branched chain
hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8
carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4
carbon atoms, are most preferred.
[0036] The term "substituted alkyl" refers to an alkyl group as
defined above having one, two, or three substituents selected from
the group consisting of halogen, trifluoromethyl, trifluoromethoxy,
alkenyl, alkynyl, nitro, cyano, keto (.dbd.O), --OR.sub.a,
--SR.sub.a, --NR.sub.aR.sub.b, --NR.sub.aSO.sub.2R.sub.c,
--SO.sub.2R.sub.c, --SO.sub.2NR.sub.aR.sub.b, --CO.sub.2R.sub.a,
--C(.dbd.O)R.sub.a, --C(.dbd.O)NR.sub.aR.sub.b,
--OC(.dbd.O)R.sub.a, --OC(.dbd.O)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aCO.sub.2R.sub.b, cycloalkyl,
heterocyclo, aryl, and heteroaryl, wherein R.sub.a and R.sub.b are
independently selected from hydrogen, alkyl, alkenyl, cycloalkyl,
heterocyclo, aryl, and heteroaryl, and R.sub.c is selected from
alkyl, alkenyl, cycloalkyl, heterocyclo, aryl and heteroaryl. When
a substituted alkyl (and/or R.sub.a, R.sub.b and R.sub.c) includes
a cycloalkyl, heterocyclo, aryl, or heteroaryl substituent, said
ringed systems are as defined below and thus may in turn have zero
to three substituents (preferably 0-2 substituents), also as
defined below. When R.sub.a, R.sub.b or R.sub.c is an alkyl or
alkenyl, said alkyl or alkenyl may optionally be substituted with
1-3 of halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano,
keto (.dbd.O), OH, --O(alkyl), phenyloxy, benzyloxy, SH,
--S(alkyl), NH.sub.2, --NH(alkyl), --N(alkyl).sub.2,
--NHSO.sub.2(alkyl), --SO.sub.2(alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(alkyl), --SO.sub.2N(alkyl).sub.2, --CO.sub.2H,
--CO.sub.2(alkyl), --C(.dbd.O)H, --C(.dbd.O)alkyl,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(alkyl),
--C(.dbd.O)N(alkyl).sub.2, --OC(.dbd.O)alkyl, --OC(.dbd.O)NH.sub.2,
--OC(.dbd.O)NH(alkyl), --NHC(.dbd.O)alkyl, and/or
--NHCO.sub.2(alkyl).
[0037] When the term "alkyl" is used in conjunction with another
group such as in "arylalkyl" or "cycloalkylalkyl," such reference
is intended to refer to a substituted alkyl in which at least one
of the substituents is the specifically-named group, i.e., the
group is bonded through an alkyl chain. For example, the term
arylalkyl includes benzyl, or any other straight or branched chain
substituted alkyl having at least one aryl group attached at any
point of the alkyl chain. However, it should be understood that
when the term "alkyl" is used following a bivalent linker preceeded
by a bond designation, such as --C(.dbd.O)C.sub.1-4alkyl,
--S(O)C.sub.1-4alkyl, --CO.sub.2C.sub.1-4alkyl, and
--SO.sub.2C.sub.1-4alkyl, such references are intended to mean that
the alkyl group is attached via the linker.
[0038] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
double bond. Alkenyl groups of 2 to 6 carbon atoms and having one
double bond are most preferred.
[0039] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one
triple bond are most preferred.
[0040] The term "alkylene" refers to bivalent straight or branched
chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1
to 8 carbon atoms, e.g., {--CH.sub.2--}.sub.n, wherein n is 1 to
12, preferably 1-8. Lower alkylene groups, that is, alkylene groups
of 1 to 4 carbon atoms, are most preferred. The terms "alkenylene"
and "alkynylene" refer to bivalent radicals of alkenyl and alknyl
groups, respectively, as defined above.
[0041] When reference is made to a substituted alkylene,
alkenylene, or alkynylene group, these groups are substituted with
one to three substitutents as defined above for alkyl groups. A
substituted alkylene, alkenylene, or alkynylene may have a ringed
substituent attached in a spiro fashion as in ##STR4## and so
forth.
[0042] The term "alkoxy" refers to an alkyl, alkenyl, substituted
alkyl, or substituted alkenyl group bonded through an oxygen atom
(--O--). For example, the term "alkoxy" includes the groups
--O--C.sub.1-12alkyl, --O--C.sub.2-8alkenyl, --S--CH.sub.2aryl, and
so forth.
[0043] The term "alkylthio" refers to an alkyl, alkenyl,
substituted alkyl, or substituted alkenyl group bonded through a
sulfur (--S--) atom. For example, the term "alkylthio" includes the
groups --S--(CH.sub.2)CH.sub.3, --S--CH.sub.2aryl, etc.
[0044] The term "alkylamino" refers to an alkyl, alkenyl,
substituted alkyl or substituted alkenyl group bonded through a
nitrogen (--NR'--) group. For example, the term "alkylamino"
includes the groups --NR'--C.sub.1-12alkyl and
--NR'--CH.sub.2-aryl, etc. (where R' is hydrogen, alkyl or
substituted alkyl as defined above.) When a subscript is used with
reference to an alkylamino group, the subscript refers to the total
number of carbon atoms attached to the nitrogen atom. Thus, for
example, C.sub.1-6alkylamino includes groups such as
--NHC.sub.1-6alkyl, --N(C.sub.1-3alkyl).sub.2,
--N(C.sub.1-2alkyl)(C.sub.1-4alkyl), and so forth. "Amino" refers
to the group --NH.sub.2. The term "aminoalkyl" means a substituted
alkyl having at least one amino substituent (e.g.,
C.sub.1-2aminoalkyl includes --CH.sub.2--NH.sub.2,
--CH.sub.2--CH.sub.2--NH.sub.2, -- and --CH(NH.sub.2)CH.sub.3.)
"Alkylaminoalkyl" means a substituted alkyl having at least one
alkylamino substituent.
[0045] When a subscript is used as in C.sub.1-8alkyl, the subscript
refers to the number of carbon atoms the group may contain. Zero
when used in a subscript denotes a bond, e.g., C.sub.0-4alkyl
refers to a bond or an alkyl of 1 to 4 carbon atoms. Thus, for
example, "C.sub.1-6alkyl" refers to straight and branched chain
alkyl groups with one to six carbon atoms, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and so forth.
"Hydroxy(C.sub.0-2alkyl)" includes hydroxy, hydroxymethyl, and
hydroxyethyl. Similarly, "phenyl(C.sub.0-2alkyl)" includes phenyl,
phenylmethyl, and phenylethyl.
[0046] When used with alkoxy, thioalkyl, or alkylamino (or
aminoalkyl), a subscript refers to the number of carbon atoms that
the group may contain in addition to heteroatoms. Thus, for
example, monovalent C.sub.1-2alkylamino includes the groups
--NH--CH.sub.3, --NH--CH.sub.2--CH.sub.3, and --N(CH.sub.3).sub.2.
A lower alkylamino comprises an alkylamino having one to four
carbon atoms.
[0047] The alkoxy, alkylthio, or alkylamino groups may be
monovalent or bivalent. By "monovalent" it is meant that the group
has a valency (i.e., power to combine with another group), of one,
and by "bivalent" it is meant that the group has a valency of two.
For example, a monovalent alkoxy includes groups such as
--O--C.sub.1-2alkyl, whereas a bivalent alkoxy includes groups such
as --O--C.sub.1-2alkylene-, etc.
[0048] The term "acyl" refers to a group having a carbonyl ##STR5##
linked to an organic group i.e., ##STR6## wherein R.sub.d may be
selected from alkyl, alkenyl, substituted alkyl, substituted
alkenyl, aryl, heterocyclo, cycloalkyl, and heteroaryl, as defined
herein.
[0049] The term "alkoxycarbonyl" refers to a group having a carboxy
or ester group ##STR7## linked to an organic radical, i.e.,
##STR8## wherein R.sub.d is as defined above for acyl.
[0050] The term "carbamyl" refers to a functional group in which a
nitrogen atom is directly bonded to a carbonyl, i.e., as in
--NR.sub.eC(.dbd.O)R.sub.f or --C(.dbd.O)NR.sub.eR.sub.f, wherein
R.sub.e and R.sub.f can be hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkoxy, cycloalkyl, aryl,
heterocyclo, or heteroaryl, or when attached to the same nitrogen
atom, R.sub.e and R.sub.f may join to form a ring.
[0051] The term "halo" or "halogen" refers to chloro, bromo, fluoro
and iodo.
[0052] The term "haloalkyl" means a substituted alkyl having one or
more halo substituents. For example, "haloalkyl" includes mono, bi,
and trifluoromethyl.
[0053] The term "haloalkoxy" means an alkoxy group having one or
more halo substituents. For example, "haloalkoxy" includes
OCF.sub.3.
[0054] The term "sulfonyl" refers to a sulphoxide group (i.e.,
--S(O).sub.1-2) linked to an organic radical R.sub.c, as defined
above.
[0055] The term "sulfonamidyl" or "sulfonamido" refers to the group
--S(O).sub.2NR.sub.eR.sub.f, wherein R.sub.e and R.sub.f are as
defined above in the definition for carbamyl. Preferably when one
of R.sub.e and R.sub.f is optionally substituted heteroaryl or
heterocyclo (as defined below), the other of R.sub.e and R.sub.f is
hydrogen, alkyl, or substituted alkyl.
[0056] The term "cycloalkyl" refers to fully saturated and
partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to
7 carbon atoms. The term "cycloalkyl" includes such rings having
zero to three substituents (preferably 0-2 substituents), selected
from 1) R.sub.g; and 2) C.sub.1-6 alkyl substituted with one to
three R.sub.g, wherein R.sub.g is selected from the group
consisting of halogen, alkyl, alkenyl, substituted alkenyl,
alkynyl, nitro, cyano, keto (.dbd.O), --OR.sub.a, --SR.sub.a,
--NR.sub.aR.sub.b, --NR.sub.aSO.sub.2R.sub.c, --SO.sub.2R.sub.c,
--SO.sub.2NR.sub.aR.sub.b, --CO.sub.2R.sub.a, --C(.dbd.O)R.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b, --OC(.dbd.O)R.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aCO.sub.2R.sub.b, aryl, heteroaryl, heterocyclo, and/or
another 4 to 7 membered cycloalkyl ring, wherein R.sub.a, R.sub.b
and R.sub.c are defined as above. When R.sub.a, R.sub.b and R.sub.c
are selected from an alkyl or alkenyl group, such groups are in
turn optionally substituted as set forth above in the definition
for substituted alkyl. The term "cycloalkyl" also includes such
rings having a second ring fused thereto (e.g., including benzo,
heterocyclo, or heteroaryl rings) or having a carbon-carbon bridge
of 3 to 4 carbon atoms. When a cycloalkyl has a second ring fused
thereto or is substituted with a further ring, i.e., aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo,
heterocycloalkyl, cycloalkylalkyl, or a further cycloalkyl ring,
such ring in turn may be substituted with one to two C.sub.0-6alkyl
substituted with one to two of (or bonded to one of) halogen,
tirfluoromethyl, C.sub.2-6alkenyl, nitro, cyano, keto (.dbd.O), OH,
--O(alkyl), phenyloxy, benzyloxy, SH, --S(alkyl), NH.sub.2,
--NH(alkyl), --N(alkyl).sub.2, --NHSO.sub.2(alkyl),
--SO.sub.2(alkyl), --SO.sub.2NH.sub.2, --SO.sub.2NH(alkyl),
--SO.sub.2N(alkyl).sub.2, --CO.sub.2H, --CO.sub.2(alkyl),
--C(.dbd.O)H, --C(.dbd.O)alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(alkyl), --C(.dbd.O)N(alkyl).sub.2, --OC(.dbd.O)alkyl,
--OC(.dbd.O)NH.sub.2, --OC(.dbd.O)NH(alkyl), --NHC(.dbd.O)alkyl,
and --NHCO.sub.2(alkyl).
[0057] Thus, the term "cycloalkyl" includes cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.,
as well as the following ring systems, ##STR9## and the like, which
optionally may be substituted at any available atoms of the
ring(s).
[0058] The term "aryl" refers to phenyl, biphenyl, 1-naphthyl, and
2-naphthyl, with phenyl being preferred. The term "aryl" includes
such rings having zero to three substituents (preferably 0-2
substituents), selected from the group consisting of 1) R.sub.h;
and 2) C.sub.1-6 alkyl substituted with one to three R.sub.g,
wherein R.sub.g is as defined above for cycloalkyl, and R.sub.h is
selected from the same groups as R.sub.g but does not include keto
(.dbd.O). Additionally, two substituents attached to an aryl,
particularly a phenyl group, may join to form a further ring such
as a fused or spiro-ring, e.g., cyclopentyl or cyclohexyl, or fused
heterocyclo or heteroaryl. When an aryl is substituted with a
further ring, such ring in turn may be substituted with one to two
C.sub.0-6alkyl substituted with one to two of (or bonded to one of)
halogen, tirfluoromethyl, C.sub.2-6alkenyl, nitro, cyano, keto
(.dbd.O), OH, --O(alkyl), phenyloxy, benzyloxy, SH, --S(alkyl),
NH.sub.2, --NH(alkyl), --N(alkyl).sub.2, --NHSO.sub.2(alkyl),
--SO.sub.2(alkyl), --SO.sub.2NH.sub.2, --SO.sub.2NH(alkyl),
--SO.sub.2N(alkyl).sub.2, --CO.sub.2H, --CO.sub.2(alkyl),
--C(.dbd.O)H, --C(.dbd.O)alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(alkyl), --C(.dbd.O)N(alkyl).sub.2, --OC(.dbd.O)alkyl,
--OC(.dbd.O)NH.sub.2, --OC(.dbd.O)NH(alkyl), --NHC(.dbd.O)alkyl,
and --NHCO.sub.2(alkyl).
[0059] Thus, examples of aryl groups include: ##STR10## the like,
which optionally may be substituted at any available carbon or
nitrogen atom.
[0060] The term "heterocyclo" or "heterocyclic" refers to
substituted and unsubstituted non-aromatic 3 to 7 membered
monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15
membered tricyclic groups, in which at least one of the rings has
at least one heteroatom (O, S or N). Each ring of the heterocyclo
group containing a heteroatom can contain one or two oxygen or
sulfur atoms and/or from one to four nitrogen atoms provided that
the total number of heteroatoms in each ring is four or less, and
further provided that the ring contains at least one carbon atom.
The fused rings completing bicyclic and tricyclic groups may
contain only carbon atoms and may be saturated, partially
saturated, or unsaturated. The nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen atoms may optionally be
quaternized. The heterocyclo group may be attached at any available
nitrogen or carbon atom. The heterocyclic ring may contain zero to
three substituents (preferably 0-2 substituents), selected from 1)
R.sub.g; and 2) C.sub.1-6 alkyl substituted with one to three
R.sub.g, wherein R.sub.g is defined as above for cycloalkyl groups.
Additionally, when a heterocyclo is substituted with a further
ring, such ring in turn may be substituted with one to two
C.sub.0-6alkyl substituted with one to two of (or bonded to one of)
halogen, tirfluoromethyl, C.sub.2-6alkenyl, nitro, cyano, keto
(.dbd.O), OH, --O(alkyl), phenyloxy, benzyloxy, SH, --S(alkyl),
NH.sub.2, --NH(alkyl), --N(alkyl).sub.2, --NHSO.sub.2(alkyl),
--SO.sub.2(alkyl), --SO.sub.2NH.sub.2, --SO.sub.2NH(alkyl),
--SO.sub.2N(alkyl).sub.2, --CO.sub.2H, --CO.sub.2(alkyl),
--C(.dbd.O)H, --C(.dbd.O)alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(alkyl), --C(.dbd.O)N(alkyl).sub.2, --OC(.dbd.O)alkyl,
--OC(.dbd.O)NH.sub.2, --OC(.dbd.O)NH(alkyl), --NHC(.dbd.O)alkyl,
and --NHCO.sub.2(alkyl).
[0061] Thus, exemplary heterocyclic groups include, without
limitation: ##STR11## and the like, which optionally may be
substituted at any available carbon or nitrogen atom.
[0062] The term "heteroaryl" refers to substituted and
unsubstituted aromatic 5 to 7 membered monocyclic groups, 9 or 10
membered bicyclic groups, and 11 to 14 membered tricyclic groups
which have at least one heteroatom (O, S or N) in at least one of
the rings. Each ring of the heteroaryl group containing a
heteroatom can contain one or two oxygen or sulfur atoms and/or
from one to four nitrogen atoms provided that the total number of
heteroatoms in each ring is four or less and each ring has at least
one carbon atom. The fused rings completing the bicyclic and
tricyclic groups may contain only carbon atoms and may be
saturated, partially saturated, or unsaturated. The nitrogen and
sulfur atoms may optionally be oxidized and the nitrogen atoms may
optionally be quaternized. Heteroaryl groups which are bicyclic or
tricyclic must include at least one fully aromatic ring but the
other fused ring or rings may be aromatic or non-aromatic. The
heteroaryl group may be attached at any available nitrogen or
carbon atom of any ring. The heteroaryl ring system may contain
zero to three substituents (preferably 0-2 substituents), selected
from 1) R.sub.h; and 2) C.sub.1-6 alkyl substituted with one to
three R.sub.g, wherein R.sub.g and R.sub.h are defined above as for
aryl groups. Additionally, when a heteroaryl is substituted with a
further ring, such ring in turn may be substituted with one to two
C.sub.0-6alkyl substituted with one to two of (or bonded to one of)
halogen, tirfluoromethyl, C.sub.2-6alkenyl, nitro, cyano, keto
(.dbd.O), OH, --O(alkyl), phenyloxy, benzyloxy, SH, --S(alkyl),
NH.sub.2, --NH(alkyl), --N(alkyl).sub.2, --NHSO.sub.2(alkyl),
--SO.sub.2(alkyl), --SO.sub.2NH.sub.2, --SO.sub.2NH(alkyl),
--SO.sub.2N(alkyl).sub.2, --CO.sub.2H, --CO.sub.2(alkyl),
--C(.dbd.O)H, --C(.dbd.O)alkyl, --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(alkyl), --C(.dbd.O)N(alkyl).sub.2, --OC(.dbd.O)alkyl,
--OC(.dbd.O)NH.sub.2, --OC(.dbd.O)NH(alkyl), --NHC(.dbd.O)alkyl,
and --NHCO.sub.2(alkyl).
[0063] Examples of heteroaryl rings include ##STR12## ##STR13## and
the like, which optionally may be substituted at any available
carbon or nitrogen atom.
[0064] The term "carbocyclic" refers to optionally substituted
aromatic or non-aromatic 3 to 7 membered monocyclic and 7 to 11
membered bicyclic groups, in which all atoms of the ring or rings
are carbon atoms. A carbocyclic ring system may optionally be
substituted as defined above for aryl and cycloalkyl groups.
[0065] When the term "unsaturated" is used herein to refer to a
ring or group, the ring or group may be fully unsaturated or
partially unsaturated.
[0066] When reference is made to a specifically-named ringed group,
such as cyclohexyl, phenyl, morpholinyl, oxazolyl, and the like, it
should be understood that, unless the presence or absence of
substituents is otherwise specifically stated, these groups
optionally may be substituted as recited above for the
corresponding genus of rings in which they belong.
[0067] When reference is made generally to a monocyclic or bicyclic
ring system, such reference is intended to include cycloalkyl,
aryl, heterocyclo, and heteroaryl rings, as defined above.
[0068] The term "metal ion" refers to alkali metal ions such as
sodium, potassium or lithium and alkaline earth metal ions such as
magnesium and calcium, as well as zinc and aluminum.
[0069] Whenever a bond appears in a formula as a dashed-double
bond, i.e., with one bond appearing as a dash as in ##STR14## it
should be understood that such bonds may be selected from single or
double bonds, as appropriate given the selections for adjacent
atoms and bonds.
[0070] Multiple substituents may be selected for any compound
within the scope of this invention; however, advantageously
substituents are selected so that the compounds of formula (I) have
a molecular weight of less than 1,500. More preferred are compounds
having a molecular weight of less than 1,000, and even more
preferred are compounds having a molecular of less than 500.
[0071] It should be understood that one skilled in the field may
make various substitutions for each of the groups recited in the
claims herein, without departing from the spirit or scope of the
invention.
[0072] Throughout the specification, groups and substituents
thereof may be chosen by one skilled in the field to provide stable
moieties and compounds.
[0073] The compounds of the present invention form salts which are
also within the scope of this invention. Unless otherwise
indicated, reference to an inventive compound is understood to
include reference to salts thereof. The term "salt(s)" denotes
acidic and/or basic salts formed with inorganic and/or organic
acids and bases. In addition, the term "salt(s) may include
zwitterions (inner salts), e.g., when a compound of the present
invention contains both a basic moiety, such as an amine or a
pyridine or imidazole ring, and an acidic moiety, such as a
carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic,
physiologically acceptable) salts are preferred, such as, for
example, acceptable metal and amine salts in which the cation does
not contribute significantly to the toxicity or biological activity
of the salt. However, other salts may be useful, e.g., in isolation
or purification steps which may be employed during preparation, and
thus, are contemplated within the scope of the invention. Salts of
the compounds of the present invention may be formed, for example,
by reacting a compound of the present invention with an amount of
acid or base, such as an equivalent amount, in a medium such as one
in which the salt precipitates or in an aqueous medium followed by
lyophilization.
[0074] Exemplary acid addition salts include acetates (such as
those formed with acetic acid or trihaloacetic acid, for example,
trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates, dodecylsulfates, ethanesulfonates, fumarates,
glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, hydrochlorides (formed with hydrochloric acid),
hydrobromides (formed with hydrogen bromide), hydroiodides,
2-hydroxyethanesulfonates, lactates, maleates (formed with maleic
acid), methanesulfonates (formed with methanesulfonic acid),
2-naphthalenesulfonates, nicotinates, nitrates, oxalates,
pectinates, persulfates, 3-phenylpropionates, phosphates, picrates,
pivalates, propionates, salicylates, succinates, sulfates (such as
those formed with sulfuric acid), sulfonates (such as those
mentioned herein), tartrates, thiocyanates, toluenesulfonates such
as tosylates, undecanoates, and the like.
[0075] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts; alkaline earth
metal salts such as calcium and magnesium salts; barium, zinc, and
aluminum salts; salts with organic bases (for example, organic
amines) such as trialkylamines such as triethylamine, procaine,
dibenzylamine, N-benzyl-.beta.-phenethylamine, 1-ephenamine,
N,N'-dibenzylethylene-diamine, dehydroabietylamine,
N-ethylpiperidine, benzylamine, dicyclohexylamine or similar
pharmaceutically acceptable amines and salts with amino acids such
as arginine, lysine and the like. Basic nitrogen-containing groups
may be quaternized with agents such as lower alkyl halides (e.g.,
methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),
dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl
sulfates), long chain halides (e.g., decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides), aralkyl halides (e.g.,
benzyl and phenethyl bromides), and others. Preferred salts include
monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or
nitrate.
[0076] Prodrugs and solvates of the inventive compounds are also
contemplated. The term "prodrug" denotes a compound which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of the present
invention, and/or a salt and/or solvate thereof. Various forms of
prodrugs are well known in the art. For examples of such prodrug
derivatives, see:
[0077] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K.
Widder, et al (Acamedic Press, 1985);
[0078] b) A Textbook of Drug Design and Development, edited by
Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and
Application of Prodrugs," by H. Bundgaard, 113-191 (1991); and
[0079] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38
(1992), each of which is incorporated herein by reference.
[0080] Compounds containing a carboxy group can form
physiologically hydrolyzable esters which serve as prodrugs by
being hydrolyzed in the body to yield the present invention
compounds per se. Such prodrugs are preferably administered orally
since hydrolysis in many instances occurs principally under the
influence of the digestive enzymes. Parenteral administration may
be used where the ester per se is active, or in those instances
where hydrolysis occurs in the blood. Examples of physiologically
hydrolyzable esters of compounds of the present invention include
C.sub.1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,
methoxymethyl, C.sub.1-6alkanoyloxy-C.sub.1-6alkyl, e.g.
acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl,
C.sub.1-6alkoxycarbonyloxy-C.sub.1-6alkyl, e.g.
methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
glycyloxymethyl, phenylglycyloxymethyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well known
physiologically hydrolyzable esters used, for example, in the
penicillin and cephalosporin arts. Such esters may be prepared by
conventional techniques known in the art.
[0081] Compounds of the present invention or salts thereof may
exist in their tautomeric form, in which hydrogen atoms are
transposed to other parts of the molecules and the chemical bonds
between the atoms of the molecules are consequently rearranged. It
should be understood that the all tautomeric forms, insofar as they
may exist, are included within the invention. Additionally,
inventive compounds may have trans and cis isomers and may contain
one or more chiral centers, therefore existing in enantiomeric and
diastereomeric forms. The invention includes all such isomers, as
well as mixtures of cis and trans isomers, mixtures of
diastereomers and racemic mixtures of enantiomers (optical
isomers). When no specific mention is made of the configuration
(cis, trans or R or S) of a compound (or of an asymmetric carbon),
then any one of the isomers or a mixture of more than one isomer is
intended. The processes for preparation can use racemates,
enantiomers or diastereomers as starting materials. When
enantiomeric or diastereomeric products are prepared, they can be
separated by conventional methods for example, chromatographic or
fractional crystallization.
[0082] The compounds of the instant invention may, for example, be
in the free or hydrate form, and may be obtained by methods
exemplified by the following descriptions.
Preferred Compounds
[0083] The methods of the invention preferably comprise
administration of compounds of formula (I), ##STR15## or
pharmaceutically-acceptable salts, hydrates, and prodrugs thereof,
in which:
[0084] A is selected from phenyl, oxazolyl, thiazolyl,
isothiazolyl, imidazolyl, furyl, thienyl, thiadiazolyl,
oxadiazolyl, tetrazolyl, triazolyl, diazolyl, pyrrolyl, and
pyrazolyl, said ring A being optionally substituted with up to two
groups selected from halogen, C.sub.1-4alkyl, haloalkyl,
haloalkoxy, OH, C.sub.1-4alkoxy, C.sub.1-4alkylcarbonyl, CN,
NH.sub.2, NH(C.sub.1-4alkyl), and N(alkyl).sub.2;
[0085] B is ##STR16##
[0086] D is phenyl, or A is a carbocyclic ring and D is selected
from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl,
thiophenyl, and pyrrolyl;
[0087] R.sub.1 is selected from hydrogen, C.sub.1-4alkyl, and
C.sub.1-4alkyl substituted with one of halogen, hydroxy, amino,
C.sub.1-3alkoxy, or C.sub.1-6alkylamino;
[0088] R.sub.2 and R.sub.3 are attached to any available carbon
atom of ring B and ring D, respectively, and at each occurrence are
independently selected from halogen, cyano, C.sub.1-4alkyl,
hydroxy(C.sub.0-4alkyl), CF.sub.3(C.sub.0-4alkyl),
OCF.sub.3(C.sub.0-4alkyl), cyano(C.sub.1-4alkyl),
amino(C.sub.0-4alkyl), C.sub.1-4alkoxy(C.sub.0-4alkyl),
C.sub.1-6alkylamino(C.sub.0-4alkyl), and
C.sub.1-4alkylthio(C.sub.0-4alkyl);
[0089] R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are
independently selected from hydrogen and C.sub.14alkyl;
[0090] R.sub.9 and R.sub.10 are independently selected from
hydrogen, C.sub.1-4alkyl, and C.sub.1-4alkyl substituted with one
to two R.sub.25; or alternatively, R.sub.9 and R.sub.10 taken
together may form a 3-8 membered heterocyclic ring or a five to six
membered heteroaryl ring, said ring being optionally substituted
with up to three R.sub.30;
[0091] R.sub.11 at each occurrence is independently selected from
halogen, cyano, C.sub.1-4alkyl, hydroxy(C.sub.0-4alkyl),
CF.sub.3(C.sub.0-4alkyl), OCF.sub.3(C.sub.0-4alkyl),
cyano(C.sub.1-4alkyl), amino(C.sub.0-4alkyl),
C.sub.1-4alkoxy(C.sub.0-4alkyl),
C.sub.1-6alkylamino(C.sub.0-4alkyl), and
C.sub.1-4alkylthio(C.sub.0-4alkyl), or two R.sub.11 groups may be
taken together to form a fused benzo, heteroaryl, or heterocyclic
ring, wherein said ring in turn is optionally substituted with up
to one A group and/or one to two of hydrogen, halogen,
C.sub.1-4alkyl, hydroxy(C.sub.0-4alkyl), CF.sub.3(C.sub.0-4alkyl),
OCF.sub.3(C.sub.0-4alkyl), cyano(C.sub.0-4alkyl), and
C.sub.1-4alkoxy(C.sub.0-4alkyl);
[0092] R.sub.25 is halogen, hydroxy, C.sub.1-3alkoxy, amino, or
C.sub.1-6alkylamino;
[0093] R.sub.30 is selected from C.sub.1-4alkyl, oxo (.dbd.O),
halo(C.sub.0-4alkyl), hydroxy(C.sub.0-4alkyl),
CF.sub.3(C.sub.0-4alkyl), OCF.sub.3(C.sub.0-4alkyl),
cyano(C.sub.0-4alkyl), amino(C.sub.0-4alkyl),
C.sub.1-4alkoxy(C.sub.0-4alkyl),
C.sub.1-6alkylamino(C.sub.0-4alkyl),
C.sub.1-4alkylthio(C.sub.0-4alkyl), --C(.dbd.O)C.sub.1-4alkyl, and
--CO.sub.2C.sub.1-4alkyl;
[0094] a is 0 or 1;
[0095] m is 0, 1, or 2;
[0096] n is 0, 1, 2, 3, or 4;
[0097] p is 0, 1 or 2; and
[0098] q is 0, 1, 2, 3 or 4.
[0099] The methods of the invention preferably comprise
administration of compounds of formula (I), where A is selected
from phenyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, furyl,
thienyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl,
diazolyl, pyrrolyl, and pyrazolyl, said ring A being optionally
substituted with up to two groups selected from halogen,
C.sub.1-4alkyl, trifluoromethyl, or cyano. More preferably A is
oxazolyl which is unsubstituted or substituted with C.sub.1-2alkyl,
and D is carbocyclic.
[0100] The methods of the invention preferably comprise
administration of compounds of formula (I), where B is ##STR17##
more preferably B is ##STR18## and even more preferred are
compounds where B is ##STR19## and is unsubstituted. Thus, R.sub.2
is preferably absent (or R.sub.2a is preferably hydrogen).
[0101] The methods of the invention preferably comprise
administration of compounds of formula (I), where D is selected
from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl,
thiophenyl, and pyrrolyl; more preferred are compounds where D is
phenyl.
[0102] The methods of the invention preferably comprise
administration of compounds of formula (I), where R.sub.3 is
absent, or is attached to any available carbon atom of ring D and
at each occurrence is independently selected from halogen, cyano,
C.sub.1-4alkyl, hydroxy(C.sub.0-4alkyl), CF.sub.3(C.sub.0-4alkyl),
OCF.sub.3(C.sub.0-4alkyl), cyano(C.sub.1-4alkyl),
amino(C.sub.0-4alkyl), C.sub.1-4alkoxy(C.sub.0-4alkyl),
C.sub.1-6alkylamino(C.sub.0-4alkyl), and
C.sub.1-4alkylthio(C.sub.0-4alkyl). More preferred are methods
comprising use of compounds where R.sub.3 is absent or if present,
is halogen, more preferably fluoro, wherein n is 1-4.
[0103] In the methods of the invention, preferably R.sub.6 is
selected from C.sub.1-4alkyl; more preferably methyl.
[0104] The methods of the invention preferably comprise
administration of compounds of formula (I), where R.sub.4, R.sub.5,
R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each selected from
hydrogen and C.sub.1-4alkyl; more preferably each of said groups is
hydrogen.
[0105] The methods of the invention preferably comprise
administration of compounds of formula (I), where R.sub.11 is
selected from halogen, cyano, C.sub.1-4alkyl, CF.sub.3, OCF.sub.3
and C.sub.1-4alkoxy, and q is 0 or 1.
[0106] Also preferred in practicing the methods of the invention
are compounds having the formula (Ia), ##STR20## or
pharmaceutically-acceptable salts, hydrates, or prodrugs thereof,
in which:
[0107] A is selected from phenyl, oxazolyl, thiazolyl,
isothiazolyl, imidazolyl, furyl, thienyl, thiadiazolyl,
oxadiazolyl, tetrazolyl, triazolyl, diazolyl, pyrrolyl, and
pyrazolyl, said ring A being optionally substituted with up to two
groups selected from halogen, NO.sub.2, C.sub.1-4alkyl, haloalkyl,
haloalkoxy, OH, C.sub.1-4alkoxy, C.sub.1-4alkylcarbonyl, CN,
NH.sub.2, NH(C.sub.1-4alkyl), and N(alkyl).sub.2;
[0108] D is phenyl, or when A is phenyl, then D is selected from
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl,
and pyrrolyl;
[0109] R.sub.2a is selected from hydrogen, halogen, and
C.sub.1-4alkyl;
[0110] R.sub.3 is selected from halogen, C.sub.1-4alkyl, CF.sub.3,
OCF.sub.3, cyano, and C.sub.1-3alkoxy;
[0111] R.sub.6 is C.sub.1-4alkyl;
[0112] R.sub.11 is selected from hydrogen, halogen, C.sub.1-4alkyl,
hydroxy(C.sub.0-4alkyl), CF.sub.3(C.sub.0-4alkyl),
OCF.sub.3(C.sub.0-4alkyl), cyano(C.sub.0-4alkyl),
amino(C.sub.0-4alkyl), C.sub.1-3alkoxy(C.sub.0-4alkyl), and
C.sub.1-6alkylamino(C.sub.0-4alkyl), or two R.sub.11 groups may be
taken together to form a fused benzo, heteroaryl, or heterocyclic
ring, wherein said ring in turn is optionally substituted with up
to one A group and/or one to two of hydrogen, halogen,
C.sub.1-4alkyl, hydroxy(C.sub.0-4alkyl), CF.sub.3(C.sub.0-4alkyl),
OCF.sub.3(C.sub.0-4alkyl), cyano(C.sub.0-4alkyl), and
C.sub.1-4alkoxy(C.sub.0-4alkyl);
[0113] R.sub.9 and R.sub.10 are independently selected from
hydrogen and C.sub.1-4alkyl;
[0114] a is 0 or 1;
[0115] n is 0, 1, 2, 3, or 4;
[0116] p is 0, 1 or 2; and
[0117] q is 0, 1, or 2.
[0118] Most preferred are the inventive methods comprising
administration of the compounds as immediately defined above,
wherein A is oxazolyl that is unsubstituted or substituted with
C.sub.1-2alkyl; D is phenyl; R.sub.2a is hydrogen; R.sub.3 is
absent (n is 0), or R.sub.3 is halogen, more preferably fluoro (and
n is 1-4); R.sub.6 is methyl; R.sub.11 is hydrogen, halogen, or
methoxy; R.sub.9 and R.sub.10 are hydrogen; a is 0 or 1; and p is
1.
[0119] The invention also relates to preferred compounds of the
present invention, exemplified herein and as defined above, which
have demonstrated activity in inhibiting Factor VIIa with IC.sub.50
values (concentration required to inhibit 50% of specific binding)
below 1 .mu.M, and more preferred compounds that have demonstrated
IC.sub.50 values of below 500 nM.
Methods of Preparation
[0120] The compounds of the present invention may be synthesized
using conventional techniques known in the art. Advantageously,
these compounds are conveniently synthesized from readily-available
starting materials. Additionally, illustrative general synthetic
schemes for making compounds of the present invention are set forth
below, and methods for making the compounds useful to the invention
are also set forth in the Examples that follow hereinafter. In
these schemes, the group Q may designate the substituent R.sub.11
or an appropriate precursor thereto, which one skilled in the field
may select as appropriate for a given reaction. Groups designated
A, D, etc., are also intended to refer to such groups as recited in
the claims.
[0121] The preparation of heterocycles useful to this invention is
described in the literature, e.g., Katritzky et al., "Comprehensive
Heterocyclic Chemistry, The Structure, Reactions, Synthesis and
Uses of Heterocyclic Compounds," (Pergamon Press New York, 1984
[1st Ed.], and 1996). Methods of preparation useful to make
compounds of this invention also may be described in U.S. Pat. No.
6,399,773, which is incorporated herein by reference. ##STR21##
[0122] Reaction of an appropriately-substituted amine (1) with a
reagent such as 1,1'-thiocarbonyldi-2(1H)-pyridone,
1,1'-thiocarbonyldiimidazole or thiophosgene in a solvent such as
methylene chloride or dioxane yields the isothiocyanate (2).
Treatment of the isothiocyanate (2) with sodium salt of cyanamide
yields the sodium salt of N-cyanothiourea (3), which is cyclized to
the substituted 1,2,4-aminotriazole (II), using an
appropriately-substituted hydrazine and a dehydrating agent such as
EDC or DCC. ##STR22##
[0123] An appropriately-substituted anine (1) can be reacted with
diphenyl cyanocarbonimidate to yield the N-cyano-O-phenylisourea
(4). Cyclization of compound (4) to the substituted triazole (II)
is achieved using an appropriately-substituted hydrazine and a
solvent such as acetonitrile. ##STR23##
[0124] Reaction of an isothiocyanate (2) with a .beta.-ketoamine in
the presence of a base such as TEA and a solvent such as dioxane
yields the thiourea (5). Reaction of the thiourea in the presence
of a dehydrating agent such as dicyclohexylcarbodiimide or EDC, in
a solvent such as dioxane or toluene, at a temperature preferably
between 60.degree. C. and 110.degree. C., yields the desired
2-aminooxazoles (III). .beta.-ketoamines are either commercially
available or can be readily prepared by several methods. One
exemplary method is reduction of azidoketones of the type described
in schemes 5a-5d, by phosphine reagents such as triphenylphosphine
in a solvent such as dioxane, followed by the addition of water or
dilute ammonium hydroxide. ##STR24##
[0125] Reaction of an appropriately-substituted isothiocyanate (2)
with an acylazide of the type described in schemes 5a-5b in the
presence of a phosphine such as triphenyphosphine in a solvent such
as DCM or dioxane at a temperature from rt to 100.degree. C., also
yields compounds (III). One skilled in the field will recognize
that caution should be exercised while handling organic azides.
##STR25##
[0126] Treatment of the .alpha.-bromoketone (6) with sodium azide
in a solvent such as acetone, generally at rt, yields the desired
.alpha.-azidoketones (7) useful as intermediates in this invention.
.alpha.-Bromoketones (6) are commercially available. Alternatively,
.alpha.-bromoketones can be readily prepared from a ketone
[CH.sub.3--C(.dbd.O)D], by (a) reaction with a brominating agent
such as bromine in acetic acid or pyridinium bromide perbromide and
30% hydrobromic acid; (b) reaction with a carboxylic acid,
isobutylchloroformate and N-methylmorpholine to provide the mixed
anhydride, which on treatment with diazomethane (CH.sub.2N.sub.2)
gives the .alpha.-diazoketone. Reaction of the .alpha.-diazoketone
with either HBr gas in a solvent such as ether or dioxane, or
aqueous 48% HBr, provides the .alpha.-bromoketone (6); or (c)
reaction with sulfuric acid and bromine which yields the
.alpha.,.alpha.-dibromoketone, which on treatment with
diethylphosphite and TEA yields the .alpha.-(mono)bromoketone (6).
##STR26##
[0127] Reaction of an aryl bromide (8) with tributyl(1-ethoxyvinyl)
tin and bis-(triphenylphosphine)palladium dichloride provides an
intermediate enol ether. Treatment of the enol ether with
N-bromosuccinamide at a temperature from 0.degree. C. to rt yields
the .alpha.-bromoketone (9). As described in Scheme 5a, treatment
of the .alpha.-bromoketone with sodium azide in acetone gives the
.alpha.-azidoketone (10). ##STR27##
[0128] Aryl boronic acids and esters of type (12), may be prepared
from the corresponding arylbromide (11) by treatment with a
palladium catalyst such as
[1,1'-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II) and
bis(pinacolato)diboron, as reported by Ishayama et al., J. Org.
Chem., 1995, 7508-7510. Aryl boronic esters may be converted to the
corresponding boronic acids by several methods including treatment
with aqueous HCl. In a variation of the synthesis, the nitrogen may
be masked as a nitro group and later reduced by several means
including metal reductions, such as by treatment with tin chloride
in HCl or by refluxing the nitro compound with zinc in the presence
of CaCl.sub.2 in a solvent such as EtOH, or in certain cases the
nitro group may be reduced by catalytic hydrogenation in the
presence of catalysts such as Pd/C. The conditions for the
reduction of nitro groups are detailed in several references
including Hudlicky, M., "Reductions in Organic Chemistry", 2nd Ed.,
ACS Monograph 188 (1996), pp. 91-101. In a second variation of the
synthesis, the aryl bromide is allowed to remain through the entire
synthesis and elaborated to the boronic acid at the end. This may
eliminate the need for a protecting group. ##STR28##
[0129] Suzuki-type cross coupling of an aryl boronic acid or ester
(12) with an appropriate bromoheterocycle (13) in the presence of a
suitable catalyst such as Pd(PPh.sub.3).sub.4 yields the desired
protected amide (14) (see, e.g., Miyaura et al., Synth. Comm.,
1981, 11(7), 513-19; Suzuki et al., J. Am. Chem. Soc. 1989,
111:513; and Kalinin, Russ. Chem. Rev., 1991, 60, 173). The amide
(13) may be deprotected as known to one skilled in the art (see,
e.g., Greene and Wuts, Protective Groups in Organic Synthesis,
(John Wiley and Sons, Inc., New York, N.Y. 1991). For example, if
the protecting group is acetyl, the product may be deprotected by
treatment with aqueous KOH at a concentration of 0.5 N to 5 N at rt
to 100.degree. C. for a period between 0.5 h and 24 h, to provide
amine (14), an intermediate for making compounds according to the
invention. Compounds (12) can be prepared as shown in Scheme 6.
##STR29##
[0130] Aryl boronic acid (12) may be reacted with 5-bromothiazole
in the presence of Pd(PPh.sub.3).sub.4, to provide (15).
Alternatively, aryl boronic acid (12) may be reacted with oxazolone
in the presence of copper (II) acetate and an amine base such as
pyridine to provide intermediate (16). Compounds (15) and (16) may
be deprotected by an appropriate method. Copper has been shown to
be an effective catalyst for cross coupling of aryl boronic acids
to N-unsubstituted heterocycles as described by Chan. et al.,
Tetrahed Lett., 1998, 39, 2933-36; and Lam et al., Tetrahed. Lett.,
1998, 39, 2941-44. This results in compounds in which the
heterocycle is attached to the aryl ring through nitrogen rather
than carbon. ##STR30##
[0131] Oxazoles may be prepared by 1,3 dipolar cycloaddition of the
corresponding aldehyde (17) and (p-tolylsulfonyl)methyl isocyanate
(TOSMIC) (19). The aldehyde may be commercially available or
prepared from the corresponding methyl group by oxidation with
reagents such as CrO.sub.3, MnO.sub.2, and ammonium cerium (IV)
nitrate. These methods are well known to one skilled in the art and
described in Hudlicky, M., Oxidations in Organic Chemistry, ACS
Monograph 186 (1990). The nitro group in intermediate (19) is
reduced to an amine (20) by methods known in the field. Synthesis
of 5-membered heterocycles by 1,3-dipolar cycloaddition is also
described by Padwa, 1,3-Dipolar Cycloaddition Chemistry, Vols. 1
& 2 (John Wiley and Sons, New York, N.Y., 1984). ##STR31##
[0132] Halonitrobenzenes (21) are either commercially available or
can be readily prepared by methods known to one skilled in the art.
Displacement of halonitrobenzenes (21) with a variety of
nucleophiles produces compounds of structure (22). In one example,
heating (21a) with a nucleophilic heterocycle such as triazole with
or without the addition of a base provides the intermediate nitro
compound which may be reduced as previously described to provide
amines (22a). Alternatively, simple organic nucleophiles such as
cyanide can be reacted with halonitrobenzene (21b) to provide an
intermediate nitro compound which can be reduced by many methods to
produce amine (22b).
Utility
[0133] The inventive compounds are inhibitors of the serine
protease FVIIa. Thus, the compounds are useful for treating or
preventing those processes, which involve the action of Factor
VIIa. As used herein with reference to the utilities described
below, the term "treating" or "treatment" encompasses either or
both responsive and prophylaxis measures, e.g., measures designed
to inhibit or delay the onset of the disease or disorder, achieve a
full or partial reduction of the symptoms or disease state, and/or
to alleviate, ameliorate, lessen, or cure the disease or disorder
and/or its symptoms.
[0134] In view of their above-referenced FVIIa inhibitory activity,
the inventive compounds are useful in treating consequences of
atherosclerotic plaque rupture including cardiovascular diseases
associated with the activation of the coagulation cascade in
thrombotic or thrombophilic states. Such diseases include arterial
thrombosis, coronary artery disease, acute coronary syndromes,
myocardial infarction, unstable angina, ischemia resulting from
vascular occlusion cerebral infarction, stroke and related cerebral
vascular diseases (including cerebrovascular accident and transient
ischemic attack). Additionally, the compounds are useful in
treating or preventing formation of atherosclerotic plaques,
transplant atherosclerosis, peripheral arterial disease and
intermittent claudication. In addition, the compounds can be used
to prevent restenosis following arterial injury induced
endogenously (by rupture of an atherosclerotic plaque), or
exogenously (by invasive cardiological procedures such as vessel
wall injury resulting from angioplasty).
[0135] In addition, the inventive compounds are useful in
preventing venous thrombosis, coagulation syndromes, deep vein
thrombosis (DVT), disseminated intravascular coagulopathy,
Kasabach-Merritt syndrome, pulmonary embolism, cerebral thrombosis,
atrial fibrillation, and cerebral embolism. The compounds are
useful in treating peripheral arterial occlusion, thromboembolic
complications of surgery (such as hip replacement, endarterectomy,
introduction of artificial heart valves, vascular grafts, and
mechanical organs), implantation or transplantation of organ,
tissue or cells, and thromboembolic complications of medications
(such as oral contraceptives, hormone replacement, and heparin,
e.g., for treating heparin-induced thrombocytopenia). The inventive
compounds are useful in preventing thrombosis associated with
artificial heart valves, stents, and ventricular enlargement
including dilated cardiac myopathy and heart failure. The compounds
are also useful in treating thrombosis due to confinement (i.e.
immobilization, hospitalization, bed rest etc.).
[0136] These compounds are also useful in preventing thrombosis and
complications in patients genetically predisposed to arterial
thrombosis or venous thrombosis (including activated protein C
resistance, FV.sub.leiden, Prothrombin 20210, elevated coagulation
factors FVII, FVIII, FIX, FX, FXI, prothrombin, TAFI and
fibrinogen), elevated levels of homocystine, and deficient levels
of antithrombin, protein C, and protein S. The inventive compounds
may be used for treating heparin-intolerant patients, including
those with congenital and acquired antithrombin III deficiencies,
heparin-induced thrombocytopenia, and those with high levels of
polymorphonuclear granulocyte elastase.
[0137] The present compounds may also be used to inhibit blood
coagulation in connection with the preparation, storage,
fractionation, or use of whole blood. For example, the compounds
may be used to maintain whole and fractionated blood in the fluid
phase such as required for analytical and biological testing, e.g.,
for ex vivo platelet and other cell function studies, bioanalytical
procedures, and quantitation of blood-containing components. The
compounds may be used as anticoagulants in extracorpeal blood
circuits, such as those necessary in dialysis and surgery (such as
coronary artery bypass surgery); for maintaining blood vessel
patency in patients undergoing transluminal coronary angioplasty,
vascular surgery including bypass grafting, arterial
reconstruction, atherectomy, vascular graft and stent patency,
tumor cell metastasis, and organ, tissue, or cell implantation and
transplantation.
[0138] In addition, the compounds of the present invention may be
useful in treating cancer and preventing the prothrombotic
complications of cancer. The compounds may be useful in treating
tumor growth, as an adjunct to chemotherapy, for preventing
angiogenesis, and for treating cancer, more particularly, cancer of
the lung, prostate, colon, breast, ovaries, and bone.
[0139] The inventive compounds may also be used in combination with
other antithrombotic or anticoagulant drugs such as thrombin
inhibitors, platelet aggregation inhibitors such as aspirin,
clopidogrel, ticlopidine or CS-747, warfarin, low molecular weight
heparins (such as LOVENOX), GPIIb/GPIIIa blockers, PAI-1 inhibitors
such as XR-330 and T-686, inhibitors of .alpha.-2-antiplasmin such
as anti-.alpha.-2-antiplasmin antibody and thromboxane receptor
antagonists (such as ifetroban), prostacyclin mimetics,
phosphodiesterase (PDE) inhibitors, such as dipyridamole or
cilostazol, PDE inhibitors in combination with thromboxane receptor
antagonists/thromboxane A synthetase inhibitors (such as
picotamide), serotonin-2-receptor antagonists (such as ketanserin),
fibrinogen receptor antagonists, hypolipidemic agents, such as
HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin,
atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin
(Nissan/Kowa), and compounds disclosed in U.S. provisional
applications No. 60/211,594 filed Jun. 15, 2000, and No. 60/211,595
filed Jun. 15, 2000; microsomal triglyceride transport protein
inhibitors (such as disclosed in U.S. Pat. Nos. 5,739,135,
5,712,279 and 5,760,246), antihypertensive agents such as
angiotensin-converting enzyme inhibitors (e.g., captopril,
lisinopril or fosinopril); angiotensin-II receptor antagonists
(e.g., irbesartan, losartan or valsartan); and/or ACE/NEP
inhibitors (e.g., omapatrilat and gemopatrilat); .beta.-blockers
(such as propranolol, nadolol and carvedilol), PDE inhibitors in
combination with aspirin, ifetroban, picotamide, ketanserin, or
clopidogrel and the like. The inventive compounds are also useful
in combination with anti-arrhythmic agents such as for atrial
fibrillation, for example, amiodarone or dofetilide.
[0140] The inventive compounds may be used in combination with
prothrombolytic agents, such as tissue plasminogen activator
(natural or recombinant), streptokinase, reteplase, activase,
lanoteplase, urokinase, prourokinase, anisolated streptokinase
plasminogen activator complex (ASPAC), animal salivary gland
plasminogen activators, and the like.
[0141] The inventive compounds may also be used in combination with
.beta.-adrenergic agonists such as albuterol, terbutaline,
formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol;
anticholinergics such as ipratropium bromide; anti-inflammatory
cortiocosteroids such as beclomethasone, triamcinolone, budesonide,
fluticasone, flunisolide or dexamethasone; and anti-inflammatory
agents such as cromolyn, nedocromil, theophylline, zileuton,
zafirlukast, monteleukast and pranleukast.
[0142] The inventive compounds may also be useful in combination
with other anticancer strategies and chemotherapies such as taxol
and/or cisplatin.
[0143] The compounds may act synergistically with one or more of
the above agents. For example, the inventive compounds may act
synergistically with the above agents to prevent reocclusion
following a successful thrombolytic therapy and/or reduce the time
to reperfusion. Thus, reduced doses of thrombolytic agent(s) may be
used, therefore minimizing potential hemorrhagic side effects.
[0144] The compounds of the present invention may be administered
by any means suitable for the condition to be treated, which may
depend on the need for site-specific treatment or quantity of drug
to be delivered. Systematic treatment is typically preferred for
cancerous conditions, although other modes of delivery are
contemplated. The compounds may be delivered orally, such as in the
form of tablets, capsules, granules, powders, or liquid
formulations including syrups; sublingually; bucally;
transdermally; parenterally, such as by subcutaneous, intravenous,
intramuscular or intrasternal injection or infusion (e.g., as
sterile injectable aqueous or non-aqueous solutions or
suspensions); nasally such as by inhalation spray; rectally such as
in the form of suppositories, or in the form of liposome particles.
Dosage unit formulations containing non-toxic, pharmaceutically
acceptable vehicles or diluents may be administered. The compounds
may be administered in a form suitable for immediate release or
extended release. Immediate release or extended release may be
achieved with suitable pharmaceutical compositions or, particularly
in the case of extended release, with devices such as subcutaneous
implants or osmotic pumps.
[0145] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The inventive compounds may be orally delivered
by sublingual and/or buccal administration, e.g., with molded,
compressed, or freeze-dried tablets. Exemplary compositions may
include fast-dissolving diluents such as mannitol, lactose,
sucrose, and/or cyclodextrins. Also included in such formulations
may be high molecular weight excipients such as celluloses
(AVICEL.RTM.) or polyethylene glycols (PEG); an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,
GANTREZ.RTM.); and agents to control release such as polyacrylic
copolymer (e.g., CARBOPOL 934.RTM.). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0146] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0147] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0148] Exemplary compositions for rectal administration include
suppositories which may contain, for example, suitable
non-irritating excipients, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0149] The effective amount of a compound of the present invention
may be determined by one of ordinary skill in the art. The specific
dose level and frequency of dosage for any particular subject may
vary and will depend upon a variety of factors, including the
activity of the specific compound employed, the metabolic stability
and length of action of that compound, the species, age, body
weight, general health, sex and diet of the subject, the mode and
time of administration, rate of excretion, drug combination, and
severity of the particular condition. An exemplary effective amount
of compounds of the present invention may be within the dosage
range of about 0.1 to about 100 mg/kg, preferably about 0.2 to
about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or
from about 1 to about 2500 mg, preferably from about 5 to about
2000 mg) on a regimen in single or 2 to 4 divided daily doses.
Factor VIIa Assay
[0150] Compound was prepared as a 5 mM stock in DMSO, diluted
further in DMSO and added directly to the assays. The DMSO
concentration for all these studies was less than 1% and compared
to DMSO vehicle controls.
[0151] Human Factor VIIa was obtained from Enzyme Research Labs
(Cat.# HFVIIA 1640). Human recombinant tissue factor (INNOVIN from
Dade Behring Cat.# B4212-100; "20 ml vial") was diluted with 8 ml
of H.sub.2O per vial and diluted further 1:30 into the 302 .mu.l
final assay volume. Tissue factor activated FVIIa enzymatic
activity was measured in a buffer containing 150 mM NaCl, 5 mM
CaCl.sub.2, 1 mM CHAPS and 1 mg/ml PEG 6000 (pH 7.4) with 1 nM
FVIIa and 100 .mu.M D-Ile-Pro-Arg-AFC (Enzyme Systems Products,
Km>200 .mu.M) 0.66% DMSO. The assay (302 .mu.l total volume) was
incubated at RT for 2 hr prior to reading fluorometric signal (Ex
405/Em 535) using a Victor 2 (Wallac) fluorescent plate reader.
[0152] To determine the compound concentration that inhibited half
of the enzyme activity (IC.sub.50), the fraction of control
activity (FCA) was plotted as a function of the inhibitor
concentration and curve to fit FCA/(1[I]/IC.sub.50). The IC.sub.50
for each compound was determined 2-4 times and the obtained values
were averaged.
[0153] Applying the above-described assays, the inventive compounds
demonstrated activity as inhibitors of Factors VIIa.
[0154] The following Examples illustrate embodiments of the
inventive compounds and starting materials, and are not intended to
limit the scope of the claims. For ease of reference, the following
abbreviations are used herein:
Abbreviations
[0155] Me=methyl [0156] Et=ethyl [0157] Ph=phenyl [0158] Bn=benzyl
[0159] t-Bu=tertiary butyl [0160] Boc=tert-butoxycarbonyl [0161]
CBZ=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl [0162]
THF=tetrahydrofuran [0163] EtOAc=ethyl acetate [0164] DMF=dimethyl
formamide [0165] i-PrOH=isopropanol [0166] DMSO=dimethyl sulfoxide
[0167] DME=1,2 dimethoxyethane [0168] DCE=1,2 dichloroethane [0169]
DCM=dichloromethane [0170] AcOH=acetic acid [0171]
TFA=trifluoroacetic acid [0172] i-Pr.sub.2NEt=diisopropylethylamine
[0173] DMAP=4-dimethylaminopyridine [0174] NMM=N-methyl morpholine
[0175] NaHCO.sub.3=sodium bicarbonate [0176] NaBH(OAc).sub.3=sodium
triacetoxyborohydride [0177] Pd/C=palladium on carbon [0178] EDC
(or EDC.HCl) or EDCI (or EDCI.HCl) or
EDAC=3-ethyl-3'-(dimethylamino)propyl-carbodiimide hydrochloride
(or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)
[0179] HOBT or HOBT.H.sub.2O=1-hydroxybenzotriazole hydrate [0180]
HOAT=1-Hydroxy-7-azabenzotriazole [0181] Pd(OAc).sub.2=Palladium
acetate [0182] CBZ-Cl=benzyl chloroformate [0183] SAX=Strong Anion
Exchanger [0184] SCX=Strong Cation Exchanger [0185]
PVP=polyvinylpyridine [0186] DCC=dicyclohexylcarbodiimide [0187]
DIC or DIPCDI=diisopropylcarbodiimide [0188] DMA=dimethyl acetamide
[0189] DIAD=diisopropyl azodicarboxylate [0190]
DIEA=diisopropylethylamine [0191] DIPEA=diisopropylethylamine
[0192] DPPF=1,1'-bis(diphenylphosphino)ferrocene [0193]
TEA=triethylamine [0194] TBS=t-butyldimethylsilyl [0195]
Tf=trifluoromethanesulfonyl [0196] L=liter [0197] mL=milliliter
[0198] .mu.L=microliter [0199] g=gram(s) [0200] h=hour(s) [0201]
mg=milligram(s) [0202] meq=milliequivalent [0203] min=minute(s)
[0204] rt or RT=room temperature [0205] conc.=concentrated [0206]
sat or sat'd=saturated [0207] TLC=thin layer chromatography [0208]
HPLC=high performance liquid chromatography [0209] RP HPLC=reverse
phase HPLC [0210] LC/MS=high performance liquid chromatography/mass
spectrometry [0211] MS or Mass Spec=mass spectrometry [0212]
MW=molecular weight [0213] mp=melting point
EXAMPLE 1
2-Amino-N-{2-[2-(3-methoxy-4-oxazol-5-yl-phenylamino)-oxazol-5-yl]-benzyl}-
-N-methyl-acetamide
[0214] ##STR32##
Part A. (2-Bromo-benzyl)-methyl-amine
[0215] ##STR33##
[0216] A solution of 2-bromobenzylbromide (9 g, 36.1 mmol) in MeOH
(60 ml) was added dropwise over 30 min. to a solution of
methylamine in MeOH (200 mL of a 2.0 M solution, 0.4 mol). The
resulting solution was stirred at rt for 2 h and concentrated. The
residue obtained was dissolved in DCM (100 mL) and successively
washed with saturated aqueous sodium carbonate, dried over sodium
sulphate, and concentrated. The resulting oil was distilled to
afford the title compound (7 g, 95%) as a colorless oil (b.p.
110.degree. C. at 0.1 mm Hg, LC/MS retention time=1.22 min.;
M.sup.+=201.92, Column: Phenominex 4.6 mm.times.50 mm. Solvent
A=10% MeOH, 90% H.sub.2O, 10 mM NH4Ac; Solvent B=90% MeOH, 10%
H.sub.2O, 10 mM NH4Ac, Flow rate: 4 mL/min, Gradient: 0% B-100% B 4
min.).
Part B. {[(2-Bromo-benzyl)-methyl-carbamoyl]-methyl}-carbamic acid
tert-butyl ester
[0217] ##STR34##
[0218] To a solution of compound 1A (1.0 g, 5 mmol) in 50 mL of DCM
was added N-Boc-glycine (950 mg, 5.4 mmol), followed by
1-hydroxy-7-azabenzotriazole (800 mg, 5.84 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.41
g, 7.38 mmol). The reaction mixture was stirred at rt for 4 hours
and concentrated under reduced pressure. The resulting oil was
dissolved in EtOAc and washed successively with saturated sodium
bicarbonate, 1N-hydrochloric acid, dried over sodium sulfate and
concentrated under reduced pressure to give the title compound (1.8
g, 99%) as a colorless oil, which was used for the subsequent step
without further purification.
Part C.
({[2-(1-Ethoxy-vinyl)-benzyl]-methyl-carbamoyl}-methyl)-carbamic
acid tert-butyl ester
[0219] ##STR35##
[0220] To a solution of compound 1B (1.0 g, 2.79 mmol) in 50 mL of
dioxane was added tributyl(1-ethoxyvinyl)tin (0.976 mL, 2.70 mmol)
and dichlorobis(triphenyl-phosphine)palladium(II) (0.160 g, 0.16
mmol). The reaction mixture was equipped with a reflux condenser
and heated at 100.degree. C. for 18 hours. More
dichlorobis-(triphenylphosphine)palladium(II) (0.100 g, 0.10 mmol)
was added and the mixture was heated at 100.degree. C. for another
2 h. The mixture was cooled to rt, concentrated under reduced
pressure and the residue obtained was taken up in EtOAc. A solution
of saturated potassium fluoride was added, and the resulting
mixture was filtered over a thin pad of Celite.RTM. into a
separating funnel. The filtrate was washed successively with
saturated potassium fluoride and water, then dried over sodium
sulfate, and concentrated under reduced pressure. The resulting oil
was purified by silica gel column chromatography to yield the title
compound as an oil (0.820 g, 84%) (LC/MS retention time=3.61 min.;
M.sup.+=349, Column: Phenominex 4.6 mm.times.50 mm, Solvent A=10%
MeOH, 90% H.sub.2O, 10 mM NH4Ac; Solvent B=90% MeOH, 10% H.sub.2O,
10 nM NH4Ac, Flow rate: 4 mL/min, Gradient: 0% B-100% B 4
min.).
Part D.
({[2-(2-Azido-acetyl)-benzyl]-methyl-carbamoyl}-methyl)-carbamic
acid tert-butyl ester
[0221] ##STR36##
[0222] To a solution of compound 1C (3.6 g, 10.3 mmol) in THF (30
mL) and water (5 mL) was added N-bromosuccinimide (2.0 g, 11.23
mmol) and the contents stirred at rt for 10 min. The solution was
concentrated under reduced pressure and partitioned between DCM and
water. The DCM layer was dried over sodium sulfate, concentrated
under reduced pressure to yield
({[2-(2-Bromo-acetyl)-benzyl]-methyl-carbamoyl}-methyl)-carbamic
acid tert-butyl ester, which was then dissolved in a mixture of
acetone (20 mL) and water (5 mL). Sodium azide (0.737 g, 11.16
mmol) was added and the reaction mixture stirred at 50.degree. C.
for 10 min., concentrated under reduced pressure, and partitioned
between DCM and water. The DCM layer was dried over sodium sulfate
and concentrated under reduced pressure. The resulting oil was
purified by silica gel column chromatography to yield the title
compound as a yellow oil (2.56 g, 68%) (LC/MS retention time=2.90
min.; M.sup.+=363, Column: Phenominex 4.6 mm.times.50 mm, Solvent
A=10% MeOH, 90% H.sub.2O, 10 mM NH4Ac; Solvent B=90% MeOH, 10%
H.sub.2O, 10 nM NH4Ac, Flow rate: 4 mL/min, Gradient: 0% B-100% B 4
min.).
Part E. 4-Nitro-2-methoxy-(.alpha.,.alpha. bisacetoxy)toluene
[0223] ##STR37##
[0224] To a 5 L three-necked round bottom flask equipped with a
mechanical stirrer was added 4-nitro-2-methoxytoluene (150.0 g,
0.8973 mol), HOAc (900 mL) and Ac.sub.2O (900 mL). The mixture was
stirred and cooled to 8.degree. C. with an acetone/ice bath.
Concentrated H.sub.2SO.sub.4 (136 mL) was carefully added while
keeping the reaction temperature below 19.degree. C. After cooling
to 0.degree. C., CrO.sub.3 (252.6 g, 2.526 mol, 2.815 equiv.) was
added portion-wise over 1 hour while maintaining the reaction
temperature between 0-10.degree. C. After the addition, the mixture
was stirred at 0.degree. C. for 30 minutes at which time the
reaction was complete. The reaction mixture was then carefully
poured into ice (1.5 kg) with stirring to give a slurry. The
remaining black gummy residue was rinsed with HOAc (3.times.100
mL), and the washes were added to the slurry. After stirring for 10
minutes, the slurry was filtered. The cake was washed with water
(3.times.400 mL) and suction dried for 17 hours to give compound 1E
(129.0 g, 51%). .sup.1H NMR (CDCl.sub.3) d 8.02 (s, 1H), 7.89 (d,
J=8.4 Hz, 1H), 7.77 (s, 1H), (d, 8.4 Hz, 1H), 3.98 (s, 3H), 2.16
(s, 6H).
Part F. 4-Nitro-2-methoxybenzaldehyde
[0225] ##STR38##
[0226] To a 2 L rounded bottom flask equipped with a condenser and
a mechanical stirrer was placed compound 1E (250.7 g, 0.8851 mol),
dioxane (300 mL) and concentrated HCl (60 mL). The reaction mixture
was heated to reflux and stirred under N.sub.2 for 20 hours. Water
(250 mL) was added dropwise while maintaining the reaction mixture
at reflux. After cooling to 0.degree. C. with an ice/water bath,
the resulting slurry was stirred for 30 minutes and then filtered.
The cake was washed with water (4.times.200 mL) and suction dried
for 17 hours to give compound 1F (146.3 g, 91%) as a yellow solid.
.sup.1H NMR (CDCl.sub.3) d 10.54 (s, 1H), 8.00 (d, J=8.3 Hz, 1H),
7.91 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 4.08 (s, 3H).
Part G. 5-(4-Nitro-2-methoxyphenyl)oxazole
[0227] ##STR39##
[0228] To a 5 L three-necked round bottom flask equipped with a
condenser and a mechanical stirrer was placed compound 1F (146.3 g,
0.8076 mol), tosylmethyl isocyanide (157.7 g, 0.8077 mol),
K.sub.2CO.sub.3 (116.6 g, 0.8075 mol) and MeOH (2.5 L). The mixture
was heated to reflux under N.sub.2 and stirred for 3 hours. Water
(1.25 L) was added drop-wise while maintaining the pot temperature
between 59-69.degree. C. The resulting slurry was cooled to rt, and
then to 5.degree. C. with an ice-water bath. After stirring for 30
minutes at 5.degree. C., the slurry was filtered. The resulting
cake was washed with water (3.times.400 mL) and dried in a vacuum
oven at 45.degree. C. for 20 hours to compound 1G (148.5 g, 84%) as
a yellow-reddish solid. .sup.1H NMR (CDCl.sub.3) d 8.02 (s, 1H),
7.97 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H), 7.86 (s, 1H), 7.78 (s,
1H), 4.11 (s, 3H).
Part H. 5-(4-Amino-2-methoxyphenyl)oxazole
[0229] ##STR40##
[0230] In a 2 L hydrogenation flask was placed compound 1G (130.0
g, 0.6131 mol), Pd/C (10%, 26.2 g) and absolute EtOH (1280 mL). The
mixture was hydrogenated at 35-45 psi H.sub.2 until the reaction
was complete. The mixture was filtered over a pad of celite (20 g)
and the cake was washed with EtOH (3.times.100 mL). The filtrate
was concentrated to a volume of 350 mL. Heptane (500 mL) was added
to the resulting slurry. After stirring for 2 hours at rt, the
slurry was filtered. The cake was washed with heptane (3.times.100
mL) and air-dried to give 1H (80.0 g). A second portion of product
(30.2 g) was recovered from the mother liquor affording a total
yield of 95%. .sup.1H NMR (CDCl.sub.3) d 7.88 (s, 1H), 7.60 (d,
J=8.4 Hz, 1H), 7.41 (s, 1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d,
J=2.1 Hz, 1H), 3.98 (bs, 2H), 3.94 (s, 3H).
Part I. 5-(4-Isothiocyanato-2-methoxy-phenyl)-oxazole
[0231] ##STR41##
[0232] To a solution of 5-(4-Amino-2-methoxyphenyl)oxazole 1H (200
mg, 1.05 mmol) in DCM (2 mL) was added thiocarbonyldiimizaole (224
mg, 1.26 mmol) and the mixture was stirred at rt for 3 h. The
mixture was concentrated under reduced pressure, and the residue
was dissolved in MeOH (9 mL) and aliquots of 3 mL were filtered
through an SCX cartridge (CUBX1HL, 500 mg cartridge, United
Chemical Technologies, Bristol Pa., USA). The filtrate was
concentrated under reduced pressure to afford 440 mg of the title
compound which was used for the subsequent step without further
purification.
Part J. Example 1
[0233] To a solution of compound 1D (0.180 g, 0.50 mmol) in 2 mL of
dioxane was added compound 1I (220 mg of crude mixture, 1 mmol)
followed by triphenylphosphine (0.140 g, 0.53 mmol). The reaction
mixture was placed in an oil bath preheated to 80.degree. C. and
stirred for 2 hour, then cooled to rt and the solvent was
evaporated. The residue was treated for 1 h at rt with a 1:1
mixture of TFA and DCM, and the mixture was concentrated under
reduced pressure. The residue was dissolved in MeOH (2 mL), loaded
onto an SCX cartridge (CUBX1HL, 500 mg cartridge, United Chemical
Technologies, Bristol Pa., USA) which was washed with MeOH (3 mL).
The title compound was eluted from the cartridge with a 2.0 M
solution of ammonia in MeOH (3 mL) and purified by preparative
reverse phase HPLC to yield 0.070 g of an orange oil. (LC/MS
retention time=2.93 min.; MH.sup.+=435, Column: Phenominex 4.6
mm.times.50 mm, Solvent A=10% MeOH, 90% H.sub.2O, 10 mM NH4Ac;
Solvent B=90% MeOH, 10% H.sub.2O, 10 mM NH4Ac, Flow rate: 4 mL/min,
Gradient: 0% B-100% B 4 min.).
EXAMPLES 2-29
[0234] ##STR42##
[0235] Compounds having the above formula, wherein the group R has
the values listed in Table 1, were prepared following the procedure
set forth above for Example 1, using appropriately-substituted aryl
or heteroaryl amine in place of 5-(4-Amino-2-methoxyphenyl)oxazole
1H. TABLE-US-00001 TABLE 1 HPLC time HPLC Ex. R (min) Method
MH.sup.+ 2 ##STR43## 2.57 c 387.3 3 ##STR44## 3.11 c 429.3 4
##STR45## 3.17 c 443.32 5 ##STR46## 2.61 c 404.29 6 ##STR47## 3.26
b 443.23 7 ##STR48## 3.02 b 438.15 8 ##STR49## 2.68 b 405.21 9
##STR50## 2.44 b 405.21 10 ##STR51## 2.75 b 420.21 11 ##STR52##
2.67 b 404.21 12 ##STR53## 3.02 b 387.21 13 ##STR54## 2.7 b 408.18
14 ##STR55## 1.93 b 377.16 15 ##STR56## 2.08 b 403.22 16 ##STR57##
2.92 b 444.19 17 ##STR58## 3.21 a 453.81 18 ##STR59## 3.11 a 431.98
19 ##STR60## 2.86 a 433.95 20 ##STR61## 3.12 a 418 21 ##STR62##
3.12 a 418 22 ##STR63## 2.65 a 403.02 23 ##STR64## 2.88 a 417.03 24
##STR65## 2.79 a 415.01 25 ##STR66## 2.68 b 421.23 26 ##STR67##
2.99 b 495.18 27 ##STR68## 2.05 b 377.2 28 ##STR69## 3.12 b 471.2
29 ##STR70## 1.87 b 393.17 HPLC Conditions for Table 1: a Column:
Phenominex 4.6 .times. 5.0 mm. Solvent A = 10% MeOH, 90% H.sub.2O,
10 mM NH4Ac; Solvent B = 90% MeOH, 10% H.sub.2O, 10 mM NH4Ac. Flow
rate: 4 mL/min. Gradient: 4 min 0% B-100% B. b Column: Phenominex
ODS 4.6 .times. 5.0 mm. Solvent A = 10% MeOH, 90% H.sub.2O, 0.1%
TFA; Solvent B = 90% MeOH, 10% H.sub.2O, 0.1% TFA: Flow rate: 4
mL/min. Gradient: 4 min 0% B-100% B. c Column: Phenominex Luna C18
4.6 .times. 5.0 mm. Solvent A = 10% MeOH, 90% H.sub.2O, 0.1% TFA;
Solvent B = 90% MeOH, 10% H.sub.2O, 0.1% TFA. Flow rate: 4 mL/min.
Gradient: 4 min 0% B-100% B.
EXAMPLES 30-48
[0236] Compounds having the formulae set forth in Table 2, were
prepared following the same or similar procedures to those set
forth above for Examples 1-29, and/or in the general schemes
previously set forth herein. In the compounds shown in Table 2, the
terminal nitrogen atom on the right-hand side is intended to
designate NH.sub.2 and the central nitrogen atom NH. These
compounds are useful in the inventive methods of inhibiting Factor
VIIa. TABLE-US-00002 TABLE 2 Ex. Structure 30 ##STR71## 31
##STR72## 32 ##STR73## 33 ##STR74## 34 ##STR75## 35 ##STR76## 36
##STR77## 37 ##STR78## 38 ##STR79## 39 ##STR80## 40 ##STR81## 41
##STR82## 42 ##STR83## 43 ##STR84## 44 ##STR85## 45 ##STR86## 46
##STR87## 47 ##STR88## 48 ##STR89##
* * * * *