U.S. patent application number 10/135541 was filed with the patent office on 2003-01-02 for endothelin receptor antagonists.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Elliott, John Duncan, Weinstock, Joseph, Xiang, Jia-Ning.
Application Number | 20030004202 10/135541 |
Document ID | / |
Family ID | 24080252 |
Filed Date | 2003-01-02 |
United States Patent
Application |
20030004202 |
Kind Code |
A1 |
Elliott, John Duncan ; et
al. |
January 2, 2003 |
Endothelin receptor antagonists
Abstract
Novel N-phenyl imidazole derivatives, pharmaceutical
compositions containing these compounds and their use as endothelin
receptor antagonists are described.
Inventors: |
Elliott, John Duncan;
(Wayne, PA) ; Weinstock, Joseph; (Phoenixville,
PA) ; Xiang, Jia-Ning; (Wayne, PA) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
24080252 |
Appl. No.: |
10/135541 |
Filed: |
April 30, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10135541 |
Apr 30, 2002 |
|
|
|
08522285 |
Apr 28, 1997 |
|
|
|
Current U.S.
Class: |
514/381 ;
514/400; 548/253; 548/338.1 |
Current CPC
Class: |
C07D 405/06 20130101;
C07D 405/14 20130101; C07D 233/64 20130101; C07D 403/06
20130101 |
Class at
Publication: |
514/381 ;
514/400; 548/253; 548/338.1 |
International
Class: |
C07D 43/02; A61K
031/4178; A61K 031/4172 |
Claims
1. A compound of Formula (I): 27wherein: R.sub.1 is H,
C.sub.1-6alkyl or C.sub.1-6alkoxy; R.sub.2 is XR.sub.5,
--R.sub.8CO.sub.2R.sub.4,
--(CH.sub.2)XC(O)N(R.sub.4)S(O).sub.yR.sub.9,
--(CH.sub.2).sub.xS(O).sub.- yN(R.sub.4)C(O)R.sub.9,
--(CH.sub.2).sub.xC(O)N(R.sub.4)C(O)R.sub.9,
--(CH.sub.2).sub.nR.sub.7,
--(CH.sub.2).sub.xS(O).sub.yN(R.sub.4)S(O).sub- .yR.sub.9 or Ar; X
is O, S or N.sub.4; R.sub.3 is C.sub.1-10alkyl, XC.sub.1-10alkyl,
Ar or XAr; R.sub.4 is hydrogen or C.sub.1-6alkyl; R.sub.5 is
--R.sub.8CO.sub.2R.sub.4, --(CH.sub.2).sub.xC(O)N(R.sub.4)S(O)-
.sub.yR.sub.9, --(CH.sub.2).sub.xS(O).sub.yN(R.sub.4)C(O)R.sub.9,
--C(O)N(R.sub.4).sub.2,
--(CH.sub.2).sub.xC(O)N(R.sub.4)C(O)R.sub.9,
--(CH.sub.2).sub.nCO.sub.2R.sub.4,
--(CH.sub.2).sub.xS(O).sub.yN(R.sub.4)- S(O).sub.yR.sub.9,
--(CH.sub.2).sub.nR.sub.7, or Ar; R.sub.6 is C.sub.1-8alkyl or
--Ar; P is tetrazol-5-yl, CO.sub.2R.sub.4 or
C(O)N(R.sub.4)S(O).sub.yR.sub.9; R.sub.7 is C.sub.1-6 alkoxy,
C.sub.1-6alkyl, hydroxy, --SC.sub.1-6alkyl, --NHSO.sub.2R.sub.9,
SO.sub.2NHR.sub.9, --SO.sub.3H, --CO(NR.sub.4).sub.2, CN,
--S(O).sub.yC.sub.1-6alkyl, --PO(OR.sub.4).sub.2,
--N(R.sub.4).sub.2, --NR.sub.4CHO, --NR.sub.4COC.sub.1-6alkyl,
--NR.sub.4CON(R.sub.4).sub.2 or Ar, or R.sub.7 is tetrazolyl, which
is substituted or unsubstituted by C.sub.1-6alkyl, CF.sub.3 or
C(O)R.sub.3; R.sub.8 is C.sub.1-4alkylene, C.sub.1-4alkenylene or
C.sub.1-4alkylidene, all of which may be linear or branched;
R.sub.9 is C.sub.1-10alkyl, N(C.sub.1-8alkyl).sub.2 or Ar; n is 1
to 4; m is 0 to 3; x is 0 to 4; y is 1 or 2; Ar is: 28naphthyl,
indolyl, pyridyl, thienyl, oxazolidinyl, thiazolyl, isothiazolyl,
pyrazolyl, imidazolyl, imidazolinyl, thiazolidinyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl,
pyrrolyl, or pyrimidyl; all of which may be substituted or
unsubstituted by one or more Z.sub.1 or Z.sub.2 groups; Z.sub.1 and
Z.sub.2 are independently hydrogen, XR.sub.4, C.sub.8alkyl,
CO.sub.2R.sub.4, C(O)N(R.sub.4).sub.2, CN, NO.sub.2, F, Cl, Br, I,
N(R.sub.4).sub.2, NHC(O)R.sub.4 or tetrazolyl which may be
substituted or unsubstituted by C.sub.1-6alkyl, CF.sub.3 or
C(O)R.sub.4; A is C.dbd.O or [C(R.sub.4).sub.2].sub.q; B is
--CH.sub.2-- or --O--; and q is 1 or 2: and the dotted line
indicates the optional presence of a double bond; or a
pharmaceutically acceptable salt thereof; provided. R.sub.6 is not
thienyl; and R.sub.2 is not (CH).sub.nC.sub.1-6 alkyl, or
--CH.dbd.CHCO.sub.2R.sub.4.
2. A compound of claim 1 wherein there is an optional double bond
present; R.sub.4 is cis to P; R.sub.1 is H or C.sub.1-6alkoxy;
R.sub.2 is --OR.sub.5, --R.sub.8CO.sub.2H,
--(CH.sub.2).sub.xC(O)N(R.sub.4)S(O).sub.- yR.sub.9,
--(CH.sub.2).sub.xC(O)NHC(O)R.sub.9, --(CH.sub.2).sub.nR.sub.7, or
R.sub.2 is phenyl or pyridyl, both of which may be substituted or
unsubstituted by one or more Z.sub.1 or Z.sub.2 groups; R.sub.3 is
C.sub.1-10alkyl, C.sub.1-10alkoxy or R.sub.3 is phenyl or
pyrazolyl, both of which may be substituted or unsubtituted by
C.sub.1-6 alkoxy, Cl, Br, F or I; R.sub.4 is hydrogen or
C.sub.1-6alkyl; R.sub.5 is --R.sub.8CO.sub.2H,
--(CH.sub.2).sub.xC(O)N(R.sub.4)S(O).sub.yR.sub.9,
--(CH.sub.2).sub.xC(O)NHC(O)R.sub.9,
--(CH.sub.2).sub.nCO.sub.2R.sub.4. --(CH.sub.2).sub.nR.sub.7 or
pyridyl which may be substituted or unsubstituted by Z.sub.1;
R.sub.6 is (a), (b) or indolyl; P is CO.sub.2H or C(O)NHS(O)yRg;
R.sub.7 is C.sub.1-6 alkoxy, C.sub.1-6alkyl, piperidinyl, hydroxy,
--NHSO.sub.2R.sub.9, --CONH, --N(R.sub.4).sub.2,
--NR.sub.4CON(R.sub.4).sub.2 or R.sub.7 is thienyl, pyridyl,
pyrimidyl, phenyl, all of which may be substituted or unsubstituted
by one or more Z.sub.1 or Z.sub.2 groups or R.sub.7 is
tetrazol-5-yl or piperazinyl both of which are substituted or
unsubstituted by C.sub.1-6alkyl; R.sub.8 is C.sub.1-4alkenylene
which may be linear or branched; R.sub.9 is C.sub.1-10alkyl,
N(C.sub.1-8alkyl).sub.2 or phenyl which may be substituted or
unsubstituted by C.sub.1-8alkyl; n is 1 to 4; m is 1; x is 0 to 4;
y is 1 or 2; Z.sub.1 and Z.sub.2 are independently hydrogen,
hydroxy, C.sub.1-8alkyl, C.sub.1-6alkoxy, CO.sub.2H,
C(O)N(R.sub.4).sub.2, F, Cl, Br, I, N(R.sub.4).sub.2, or tetrazolyl
which may be substituted or unsubstituted by C.sub.1-6alkyl; A is
[C(R.sub.4).sub.2].sub.q; q is 1; and B is --O--.
3. A compound of claim 2 wherein there is an optional double bond
present; R.sub.4 is cis to P; R.sub.1 is H or C.sub.1-3alkoxy;
R.sub.2 is --(CH.sub.2).sub.xC(O)NHS(O).sub.2R.sub.9, --OR.sub.5
--O(CH.sub.2).sub.1-3CO.sub.2H or --(CH.sub.2).sub.nR.sub.7;
R.sub.3 is C.sub.1-5alkyl; R.sub.4 is hydrogen; R.sub.5 is
--(CH.sub.2).sub.xC(O)NHS- (O).sub.2R.sub.9,
--(CH.sub.2).sub.xC(O)NHC(O)R.sub.9, --(CH.sub.2).sub.nR.sub.7 or
pyridyl which may be substituted or unsubstituted by Z.sub.1;
R.sub.6 is (b); P is CO.sub.2H; R.sub.7 is hydroxy,
--NHSO.sub.2R.sub.9, --CONH(C.sub.1-5alkyl), or R.sub.7 is
tetrazol-5-yl or piperazinyl, both of which may be substituted or
unsubstituted by C.sub.1-6alkyl or R.sub.7 is thienyl, pyridyl,
pyrimidyl, or phenyl, all of which may be substituted or
unsubstituted by one or more Z.sub.1 or Z.sub.2 groups; R.sub.9 is
C.sub.1-5alkyl, N(C.sub.1-5alyl).sub.2 or R.sub.9 is phenyl which
may be substituted or unsubstituted by C.sub.1-5alkyl; n is 1 to 4;
m is 1; x is 0 to 4; Z.sub.1 and Z.sub.2 are independently
hydrogen, hydroxy, C.sub.1-6alkoxy, CO.sub.2H, C(O)NH.sub.2, F, Cl,
or tetrazolyl which may be substituted or unsubstituted by
C.sub.1-6alkyl; A is --CH.sub.2--; and B is --O--.
4. A compound of claim 1 chosen from the group consisting of:
(E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-methoxy]phenyl-1H-imidazol-5-
-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
(E)-3-[2-Butyl-1-[2-(4-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-imidazol-
-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
E-3-[2-Butyl-1-[2-(3-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-imidazol-5-
-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
E-3-[2-Butyl-1-[2-[N-(2-methylphenyl)sulfonyl]carboxamidomethoxy-4-methox-
yl
phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-
-2-propenoic acid;
E-3-[2-Butyl-1-[2-[N-(4-methylphenyl)sulfonyl]carboxami-
domethoxy-4-methoxy]
phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylened-
ioxyphenyl)methyl]-2-propenoic acid;
E-3-[2-Butyl-1-[2-(N-dimethylaminosul-
fonyl)carboxamidomethoxy-4-methoxy]phenyl-1H-irruidazol-5-yl]-2-[(2-methox-
y-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;
E-3-[2-Butyl-1-[2-(N-methanesulfonyl)carboxanridomethoxy-4-methoxy]phenyl-
-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propen-
oic acid;
E-3-[2-Butyl-1-[2-(N-t-butylsulfonyl)carboxamidomethoxy-4methoxy-
]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-
-propenoic acid;
E-3-[2-Butyl-1-[2-(N-1-propylsulfonyl)carboxamidomethoxy--
4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)-
methyl]-2-propenoic acid;
E-3-[2-Butyl-1-[2-(2-(tetrazol-5-yl)benzyloxy-4--
methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)me-
thyl]-2-propenoic acid;
E-3-[2-Butyl-1-[2-(2ethyl-3H-tetrazol-5-yl)benzylo-
xy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphen-
yl)methyl]-2-propenoic acid;
E-3-[2-Butyl-1-[2-[(4-carboxypyridin-3-yl)oxy-
]4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(3,4-methylenedioxyphenyl)methyi]-2-
-propenoic acid;
(E)-3-[2-Butyl-[1-(2-carboxymethoxy)-4-methoxy)phenyl]-1H-
-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid; or
E-3-[2-Butyl-1-[2-(3-carboxy)propoxy-4-methoxy]phenyl-1H-imidazo-
l-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid.
5. A compound of claim 1 which is
(E)-3-[2-Butyl-1-[2-(2-carboxyphenyl)met-
hoxy-4-methoxy]phenyl-1H-irridazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyp-
henyl)methyl]-2-propenoic acid;
6. A compound of claim 2 which is
(E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)]-
carboxamidomeltoxy-4-methoxyphenyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-me-
thylenedioxy)phenylmethyl]-2-propenoic acid dipotassium;
7. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
8. A compound of claim 1 for use as an endothelin receptor
antagonist.
9. A method of treatment of diseases caused by an excess of
endothelin comprising administering to a subject in need thereof,
an effective amount of an endothelin receptor antagonist of claim
1.
10. A method of treating hypertension, renal failure or
cerbrovascular disease which comprises administering to a subject
in need thereof, an effective amount of a compound of claim 1.
11. A method for the prophylaxis and treatment of radiocontrast
induced renal failure which comprises administering to a subject in
need thereof, an effective amount of a compound of claim 1.
12. A method of treatment of benign prostatic hypertrophy which
comprises administering to a subject in need thereof, an effective
amount of a compound of claim 1.
13. A method of treatment of congestive heart failure which
comprises administering to a subject in need thereof, an effective
amount of a compound of claim 1.
14. A method of treatment of migraine which comprises administering
to a subject in need thereof, an effective amount of a compound of
claim 1.
15. A method of preventing or treating restenosis which comprises
administering to a subject in need thereof, an effective amount of
a compound of claim 1.
16. A method of treatment of pulmonary hypertension which comprises
administering to a subject in need thereof, an effective amount of
a compound of claim 1.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel N-phenyl imidazole
derivatives, pharmaceutical compositions containing these compounds
and their use as endothelin receptor antagonists.
[0002] Endothelin (ET) is a highly potent vasoconstrictor peptide
synthesized and released by the vascular endothelium. Endothelin
exists as three isoforms, ET-1, ET-2 and ET-3. [Unless otherwise
stated "endothelin" shall mean any or all of the isoforms of
endothelin]. Endothelin has profound effects on the cardiovascular
system, and in particular, the coronary, renal and cerebral
circulation. Elevated or abnormal release of endothelin is
associated with smooth muscle contraction which is involved in the
pathogenesis of cardiovascular, cerebrovascular, respiratory and
renal pathophysiology. Elevated levels of endothelin have been
reported in plasma from patients with essential hypertension, acute
myocardial infarction, subarachnoid hemorrhage, atherosclerosis,
and patients with uraemia undergoing dialysis.
[0003] In vivo, endothelin has pronounced effects on blood pressure
and cardiac output. An intravenous bolus injection of ET (0.1 to 3
mmol/kg) in rats causes a transient, dose-related depressor
response (lasting 0.5 to 2 minutes) followed by a sustained,
dose-dependent rise in arterial blood pressure which can remain
elevated for 2 to 3 hours following dosing. Doses above 3 nmol/kg
in a rat often prove fatal.
[0004] Endothelin appears to produce a preferential effect in the
renal vascular bed. It produces a marked, long-lasting decrease in
renal blood flow, accompanied by a significant decrease in GFR,
urine volume, urinary sodium and potassium excretion. Endothelin
produces a sustained antinatriuretic effect, despite significant
elevations in atrial natriuretic peptide. Endothelin also
stimulates plasma renin activity. These findings suggest that ET is
involved in the regulation of renal function and is involved in a
variety of renal disorders including acute renal failure,
cyclosporine nephrotoxicity, radio contrast induced renal failure
and chronic renal failure.
[0005] Studies have shown that in vivo, the cerebral vasculature is
highly sensitive to both the vasodilator and vasoconstrictor
effects of endothelin. Therefore, ET may be an important mediator
of cerebral vasospasm, a frequent and often fatal consequence of
subarachnoid hemorrhage.
[0006] ET also exhibits direct central nervous system effects such
as severe apnea and ischemic lesions which suggests that ET may
contribute to the development of cerebral infarcts and neuronal
death.
[0007] ET has also been implicated in myocardial ischemia (Nichols
et al. Br. J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Circ.
Res., 65: 1193-1200, 1989) coronary vasospasm (Fukuda et al., Eur.
J. Pharm. 165: 301-304, 1989 and Luscher, Circ. 83: 701, 1991)
heart failure, proliferation of vascular smooth muscle cells,
(Takagi, Biochem & Biophys. Res. Commun.; 168: 537-543, 1990,
Bobek et al., Am. J. Physiol. 258:408-C415, 1990) and
atherosclerosis, (Nakaki et al., Biochem. & Biophys. Res.
Commun. 158: 880-881, 1989, and Lerinan et al. New Eng. J. of Med.
325: 997-1001, 1991). Increased levels of endothelin have been
shown after coronary balloon angioplasty (Kadel et al., No. 2491
Circ. 82: 627, 1990).
[0008] Further, endothelin has been found to be a potent
constrictor of isolated mammalian airway tissue including human
bronchus (Uchida et al., Eur J. of Pharm. 154: 227-228 1988,
LaGente, Clin. Exp. Allergy 20: 343-348, 1990; and Springall et
al., Lancet, 337: 697-701, 1991). Endothelin may play a role in the
pathogenesis of interstitial pulmonary fibrosis and associated
pulmonary hypertension, Glard et al., Third International
Conference on Endothelin, 1993, p. 34 and ARDS (Adult Respiratory
Distress Syndrome), Sanai et al., Supra, p. 112.
[0009] Endothelin has been associated with the induction of
hemorrhagic and necrotic damage in the gastric mucosa (Whittle et
al., Br. J. Pharm. 95: 1011-1013, 1988); Raynaud's phenomenon,
Cinniniello et al, Lancet 337: 114-115, 1991); Crohn's Disease and
ulcerative colitis, Munch et al., Lancet, Vol. 339, p. 381;
Migraine (Edmeads, Headache, Feb. 1991 p 127); Sepsis (Weitzberg et
al., Circ. Shock 33: 222-227, 1991; Pittet et al., Ann. Surg. 213:
262-264, 1991), Cyclosporin-induced renal failure or hypertension
(Eur. J. Pharmacol., 180: 191-192, 1990, Kidney Int, 37: 1487-1491,
1990) and endotoxin shock and other endotoxin induced diseases
(Biochem. Biophys. Res. Commun., 161: 1220-1227, 1989, Acta
Physiol. Scand. 137: 317-318, 1989) and inflammatory skin diseases.
(Clin Res. 41:451 and 484, 1993).
[0010] Endothelin has also been implicated in preclampsia of
pregnancy. Clark et al., Am. J. Obstet. Gynecol. March 1992, p.
962-968; Kamor et al., N. Eng. J. of Med., Nov. 22, 1990, p.
1486-1487; Dekker et al., Eur J. Ob. and Gyn. and Rep. Bio. 40
(1991) 215-220; Schiff et al., Am. J. Ostet. Gynecol. February
1992, p. 624-628; diabetes mellitus, Takahashi et al., Diabetologia
(1990) 33:306-310; and acute vascular rejection following kidney
transplant, Watschinger et al., Transplantation Vol. 52, No. 4,
pp.743-746.
[0011] Endothelin stimulates both bone resorption and anabolism and
may have a role in the coupling of bone remodeling. Tatrai et al.
Endocrinology, Vol. 131, p. 603-607.
[0012] Endothelin has been reported to stimulate the transport of
sperm in the uterine cavity, Casey et al., J. Clin. Endo and
Metabolism, Vol. 74, No. 1, p. 223-225, therefore endothelin
antagonists may be useful as male contraceptives. Endothelin
modulates the ovarian/menstrual cycle, Kenegsberg, J. of Clin. Endo
and Met., Vol. 74, No. 1, p. 12, and may also play a role in the
regulation of penile vascular tone in man, Lau et al., Asia Pacific
J. of Pharm., 1991, 6:287-292 and Tejada et al., J. Amer. Physio.
Soc. 1991, H1078-H1085. Endothelin also mediates a potent
contraction of human prostatic smooth muscle, Langenstroer et al.,
J. Urology, Vol. 149, p. 495-499.
[0013] Thus, endothelin receptor antagonists would offer a unique
approach toward the pharmacotherapy of hypertension, renal failure,
ischemia induced renal failure, sepsis-endotoxin induced renal
failure, prophylaxis and/or treatment of radio-contrast induced
renal failure, acute and chronic cyclosporin induced renal failure,
cerebrovascular disease, myocardial ischemia, angina, heart
failure, asthma, pulmonary hypertension, pulmonary hypertension
secondary to intrinsic pulmonary disease, atherosclerosis,
Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin
shock, endotoxin induced multiple organ failure or disseminated
intravascular coagulation, cyclosporin-induced renal failure and as
an adjunct in angioplasty for prevention of restenosis, diabetes,
preclampsia of pregnancy, bone remodeling, kidney transplant, male
contraceptives, infertility and priaprism and benign prostatic
hypertrophy.
SUMMARY OF THE INVENTION
[0014] This invention comprises compounds represented by Formula
(I) and pharmaceutical compositions containing these compounds, and
their use as endothelin receptor antagonists which are useful in
the treatment of a variety of cardiovascular and renal diseases
including but not limited to: hypertension, acute and chronic renal
failure, cyclosporine induced nephrotoxicity, benign prostatic
hypertrophy, pulmonary hypertension, migraine, stroke,
cerebrovascular vasospasm, myocardial ischemia, angina, heart
failure, atherosclerosis, and as an adjunct in angioplasty for
prevention of restenosis.
[0015] This invention further constitutes a method for antagonizing
endothelin receptors in an animal, including humans, which
comprises administering to an animal in need thereof an effective
amount of a compound of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
[0016] The compounds of this invention are represented by
structural Formula (I): 1
[0017] wherein:
[0018] R.sub.1 is H, C.sub.1-6alkyl or C.sub.1-6alkoxy;
[0019] R.sub.2 is XR.sub.5, --R.sub.8CO.sub.2R.sub.4,
--(CH.sub.2).sub.xC(O)N(R.sub.4)S(O).sub.yR.sub.9,
--(CH.sub.2).sub.xS(O).sub.yN(R.sub.4)C(O)R.sub.9,
--(CH.sub.2).sub.xC(O)N(R.sub.4)C(O)R.sub.9,
--(CH.sub.2).sub.nR.sub.7,
--(CH.sub.2).sub.xS(O).sub.yN(R.sub.4)S(O).sub.yR.sub.9 or Ar;
[0020] X is O, S or NR.sub.4;
[0021] R.sub.3 is C.sub.1-10alkyl, XC.sub.1-10alkyl, Ar or XAr,
[0022] R.sub.4 is hydrogen or C.sub.1-6alkyl;
[0023] R.sub.5 is --R.sub.8CO.sub.2R.sub.4,
--(CH.sub.2).sub.xC(O)N(R.sub.- 4)S(O).sub.yR.sub.9,
--(CH.sub.2).sub.xS(O).sub.yN(R.sub.4)C(O)R.sub.9,
--C(O)N(R.sub.4).sub.2,
--(CH.sub.2).sub.xC(O)N(R.sub.4)C(O)R.sub.9,
--(CH.sub.2).sub.xS(O).sub.yN(R.sub.4)S(O).sub.yR.sub.9,
--(CH.sub.2).sub.nCO.sub.2R.sub.4, --(CH.sub.2).sub.nR.sub.7, or
Ar;
[0024] R.sub.6 is C.sub.1-8alkyl or --Ar;
[0025] P is tetrazol-5-yl, CO.sub.2R.sub.4 or
C(O)N(R.sub.4)S(O).sub.yR.su- b.9;
[0026] R.sub.7 is C.sub.1-6alkoxy, C.sub.1-6alkyl, hydroxy,
--SC.sub.1-6alkyl, --NHSO.sub.2R.sub.9, SO.sub.2NHR.sub.9,
--SO.sub.3H, --CO(NR.sub.4).sub.2, CN, --S(O).sub.yC.sub.1-6alkyl,
--PO(OR.sub.4).sub.2, --N(R.sub.4).sub.2, --NR.sub.4CHO,
--NR.sub.4COC.sub.1-6alkyl, --NR.sub.4CON(R.sub.4).sub.2 or Ar, or
R.sub.7 is tetrazolyl, which is substituted or unsubstituted by
C.sub.1-6alkyl, CF.sub.3 or C(O)R.sub.3;
[0027] R.sub.8 is C.sub.1-4alkylene, C.sub.1-4alkenylene or
C.sub.1-4alkylidene, all of which may be linear or branched;
[0028] R.sub.9 is C.sub.1-10alkyl, N(C.sub.1-8alkyl).sub.2 or
Ar;
[0029] n is 1 to 4;
[0030] m is 0 to 3;
[0031] x is 0 to 4;
[0032] y is 1 or 2;
[0033] Ar is: 2
[0034] naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl,
thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, imidazolinyl,
thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl,
piperidinyl, piperazinyl, pyrrolyl, or pyrirnidyl; all of which may
be substituted or unsubstituted by one or more Z.sub.1 or Z.sub.2
groups;
[0035] Z.sub.1 and Z.sub.2 are independently hydrogen, XR.sub.4,
C.sub.1-8alkyl, CO.sub.2R.sub.4, C(O)N(R.sub.4).sub.2, CN,
NO.sub.2, F, Cl, Br, I, N(R.sub.4).sub.2, NIHC(O)R.sub.4 or
tetrazolyl which may be substituted or unsubstituted by
C.sub.1-6alkyl, CF.sub.3 or C(O)R.sub.4;
[0036] A is C.dbd.O or [C(R.sub.4).sub.2].sub.q;
[0037] B is --CH.sub.2-- or --O--; and
[0038] q is 1 or 2;
[0039] and the dotted line indicates the optional presence of a
double bond; or a pharmaceutically acceptable salt thereof;
[0040] provided:
[0041] R.sub.6 is not thienyl; and
[0042] R.sub.2 is not (CH).sub.nC.sub.1-6 alkyl, or
--CH.dbd.CHCO.sub.2R.sub.4.
[0043] All alkyl, alkenyl, alkynyl and alkoxy groups may be
straight or branched.
[0044] The compounds of the present invention may contain one or
more asymrnetric carbon atoms and may exist in racemic and
optically active form. All of these compounds and diastereoisomers
are contemplated to be within the scope of the present
invention.
[0045] Preferred compounds are those wherein there is an optional
double bond present; R.sub.4 is cis to P; R.sub.1 is H or
C.sub.1-6alkoxy; R.sub.2 is --OR.sub.5, --R.sub.8CO.sub.2H,
--(CH.sub.2).sub.xC(O)N(R.sub.- 4)S(O).sub.yR.sub.9,
--(CH.sub.2).sub.xC(O)NHC(O)R.sub.9, --(CH.sub.2).sub.nR.sub.7, or
R.sub.2 is phenyl or pyridyl, both of which may be substituted or
unsubstituted by one or more ZI or Z.sub.2 groups; R.sub.3 is
C.sub.1-10alkyl, C.sub.1-10alkoxy or R.sub.3 is phenyl or
pyrazolyl, both of which may be substituted or unsubtituted by
C.sub.1-6alkoxy, Cl, Br, F or I; R.sub.4 is hydrogen or
C.sub.1-6alkyl; R.sub.5 is --R.sub.8CO.sub.2H,
--(CH.sub.2).sub.xC(O)N(R.sub.4)S(O).sub.y- R.sub.9,
--(CH.sub.2).sub.xC(O)NHC(O)R.sub.9, --(CH.sub.2).sub.nCO.sub.2R.-
sub.4, --(CH.sub.2).sub.nR.sub.7 or pyridyl which may be
substituted or unsubstituted by Z.sub.1; R.sub.6 is (a), (b) or
indolyl; P is CO.sub.2H or C(O)NHS(O).sub.yR.sub.9; R.sub.7 is
C.sub.1-6 alkoxy, C.sub.1-6alkyl, piperidinyl, hydroxy,
--NHSO.sub.2R.sub.9, --CONHR.sub.4, --N(R.sub.4).sub.2,
--NR.sub.4CON(R.sub.4).sub.2 or R.sub.7 is thienyl, pyridyl,
pyrimidyl, phenyl, all of which may be substituted or unsubstituted
by one or more Z.sub.1 or Z.sub.2 groups or R.sub.7 is
tetrazol-5-yl, piperazinyl both of which are substituted or
unsubstituted by C.sub.1-6alkyl; R.sub.8 is C.sub.1-4alkenylene
which may be linear or branched; R.sub.9 is C.sub.1-10alkyl,
N(C.sub.1-8alkyl).sub.2 or phenyl which may be substituted or
unsubstituted by C.sub.1-8alkyl; n is 1 to 4; m is 1; x is 0 to 4;
y is 1 or 2; Z.sub.1 and Z.sub.2 are independently hydrogen,
hydroxy, C.sub.1-8alkyl, C.sub.1-6alkoxy, CO.sub.2H,
C(O)N(R.sub.4).sub.2, F, Cl, Br, I, N(R.sub.4).sub.2, or tetrazolyl
which may be substituted or unsubstituted by C.sub.1-6alkyl; A is
[C(R.sub.4).sub.2]q; q is 1; and B is --O--.
[0046] More preferred are compounds wherein there is an optional
double bond present; R.sub.4 is cis to P; R.sub.1 is H or
C.sub.1-3alkoxy; R.sub.2 is
--(CH.sub.2).sub.xC(O)NHS(O).sub.2R.sub.9, --OR.sub.5,
--(CH.sub.2).sub.nR.sub.7, or --O(CH.sub.2).sub.1-3CO.sub.2H;
R.sub.3 is C.sub.1-5alkyl; R.sub.4 is hydrogen; R.sub.5 is
--(CH.sub.2).sub.xC(O)NHS- (O).sub.2R.sub.9,
--(CH.sub.2).sub.xC(O)NHC(O)R.sub.9, --(CH.sub.2).sub.nR.sub.7 or
pyridyl which may be substituted or unsubstituted by Z.sub.1;
R.sub.6 is (b); P is CO.sub.2H; R.sub.7 is hydroxy,
--NHSO.sub.2R.sub.9, --CONH(C.sub.1-5alkyl), or R.sub.7 is
tetrazol-5-yl or piperazinyl, both of which may be substituted or
unsubstituted by C.sub.1-6alkyl or R.sub.7 is thienyl, pyridyl,
pyrinmidyl, or phenyl, all of which may be substituted or
unsubstituted by one or more Z.sub.1 or Z.sub.2 groups; R.sub.9 is
C.sub.1-5alkyl, N(C.sub.1-5alkyl).sub.2 or R.sub.9 is phenyl which
may be substituted or unsubstituted by C.sub.1-5alkyl; n is 1 to 4;
m is 1; x is 0 to 4; Z.sub.1 and Z.sub.2 are independently
hydrogen, hydroxy, C.sub.1-6alkoxy, CO.sub.2H, C(O)NH.sub.2, F, Cl,
or tetrazolyl which may be substituted or unsubstituted by
C.sub.1-6alkyl; A is --CH.sub.2--; and B is --O--.
[0047] Especially preferred are the following compounds:
[0048]
(E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)]carboxamidomethoxy-4-methox-
yphenyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]--
2-propenoic acid dipotassium;
[0049]
(E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-methoxy]phenyl-1H-imid-
azol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
[0050]
(E)-3-[2-Butyl-1-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-im-
idazol-5-yl]-2-[(2-methoxy-4,5-metlhylenedioxyphenyl)methyl]-2-propenoic
acid;
[0051]
(E)-3-[2-Butyl-1-[2-(4-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-im-
idazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
[0052]
E-3-[2-Butyl-1-[2-(3-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-imid-
azol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
[0053]
E-3-[2-Butyl-1-[2-[N-(2-methylphenyl)sulfonyl]carboxamidomethoxy-4--
methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)me-
thyl]-2-propenoic acid;
[0054]
E-3-[2-Butyl-1-[2-[N-(4-methylphenyl)sulfonyl]carboxamidomethoxy-4--
methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)me-
thyl]-2-propenoic acid;
[0055]
E-3-[2-Butyl-1-[2-(N-dimethylaminosulfonyl)carboxaniidomethoxy-4-me-
thoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)meth-
yl]-2-propenoic acid;
[0056]
E-3-[2-Butyl-1-[2-(N-methanesulfonyl)carboxamidomethoxy-4-methoxy]p-
henyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-p-
ropenoic acid;
[0057]
E-3-[2-Butyl-1-[2-(N-t-butylsulfonyl)carboxamiidomethoxy-4methoxyjp-
henyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-p-
ropenoic acid;
[0058]
E-3-[2-Butyl-1-[2-(N-i-propylsulfonyl)carboxamidomethoxy-4-methoxyp-
henyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-p-
ropenoic acid;
[0059]
E-3-[2-Butyl-1-[2-(2-(tetrazol-5-yl)benzyloxy-4-methoxy]phenyl-1H-i-
midazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
[0060]
E-3-[2-Butyl-1-[2-(2-ethyl-3H-tetrazol-5-yl)benzyloxy-4-methoxy]phe-
nyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-pro-
penoic acid;
[0061]
E-3-[2-Butyl-1-[2-[(4-carboxypyridin-3-yl)oxy]-4-methoxy]phenyl-1H--
imidazol-5-yl]-2-[(3,4-methylenedioxyphenyl)methyl]-2-propenoic
acid;
[0062]
(E)-3-[2-Butyl-[1-(2-carboxymethoxy)-4-methoxy)phenyl]-1H-imidazol--
5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
[0063]
E-3-[2-Butyl-1-[2-(3-carboxy)propoxy-4-methoxy]phenyl-1H-imidazol-5-
-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid;
[0064] The present invention provides compounds of Formula (I),
3
[0065] which can be prepared by reacting an aniline of Formula (2)
4
[0066] with an iminoether of Formula (3) 5
[0067] in a solvent such as dichloromethane at reflux to afford an
amidine of Formula (4). 6
[0068] An iminoether of Formula (3) may be prepared from a nitrile
of Formula (5)
R.sub.3--CN (5)
[0069] by reaction with methanolic hydrogen chloride, in a solvent
such as methyl alcohol, to provide the corresponding iminoether
hydrochloride followed by liberation of (3) by treatment with a
base such as triethylamine in a solvent such as diethyl ether.
Filtration of the resulting product to remove triethylamine
hydrochloride followed by evaporation of the solvent in vacuo
provides (3).
[0070] Reaction of an amidine of Formula (4) with
2-bromo-malondialdehyde (6) 7
[0071] in a solvent such as isopropanol containing triethylammonium
acetate at reflux affords an aldehyde of Formula (7). 8
[0072] Knoevenagel condensation of a compound such as (7) with a
half acid of Formula (8), wherein R.sub.6 is Ar, m is 1 or 2, and
R.sub.10 is C.sub.1-8alkyl, 9
[0073] in a solvent such as benzene at reflux, in the presence of
piperidinium acetate with azeotropic removal of water using a
Dean-Stark apparatus, affords an ester of Formula (9). 10
[0074] Saponification of an ester of Formula of (9) with aqueose
sodium hydroxide in a solvent such as ethanol following acidic work
up affords a compound of Formula of (1), where R.sub.4 is H, and P
is COOH.
[0075] Alternatively, hydrogenation of a compound of Formula (9)
with hydrogen gas under pressure at approximately 60 psi in the
presence of a suitable catalyst such as 10% palladium on charcoal
in a suitable solvent such as ethyl acetate or ethanol affords a
compound of Formula (10); 11
[0076] Saponification of an ester of Formula of (10) with aqeouse
sodium hydroxide in a solvent such as ehtanol following acidic work
up affords a compound of Formula of (1), where there is an optional
single bond, R.sub.4 is H, P is COOH.
[0077] An aniline of Formula (11) may be prepared by reaction of a
nitrophenol of Formula (13) 12
[0078] with bromomethyl methyl ether in a solvent such as dimethyl
formamide in the presence of a base such as sodium hydride to
afford an ether of Formula (14). 13
[0079] Reduction of an ether of Formula (14) using hydrogen in the
presence of a catalyst such as 10% palladium on charcoal in a
solvent such as ethanol affords a aniline of Formula (11). 14
[0080] For compounds of Formula (1), wherein R.sub.2 is
O(CH.sub.2).sub.nR.sub.7 (R.sub.7 is tetrazole or Ar) or
OCH.sub.2CONHSO.sub.2R.sub.6, R.sub.4 is hydrogen, P is CO.sub.2H,
an aniline of Formula (11 is reacted as described above to provide
an aldehyde of Formula (12). 15
[0081] A malonic acid half ester of Formula (8), where R.sub.6 is
(b), A is --CH.sub.2--, B is --O--, and m is 1, may be prepared
from an aldehyde such as (15) 16
[0082] by treatment with a dialkyl malonate of Formula (16),
wherein R.sub.10 is C.sub.1-8alkyl,
CH.sub.2(CO.sub.2R.sub.10).sub.2 (16)
[0083] in a solvent such as cyclohexane at reflux, in the presence
of a base such as piperidine containing a catalytic amount of
para-toluic acid, with removal of water using a Dean-Stark
apparatus to afford a product of Formula (17). 17
[0084] Reduction of a compound of Formula (17) with sodium
borohydride in a solvent such as ethanol affords a product of
Formula (18). 18
[0085] Mono saponification of an ester of Formula (18) with aqueous
potassium hydroxide in a solvent such as ethanol followed by
acidification with aqueous hydrochloric acid affords a malonic acid
derivative of Formula (8), where R.sub.6 is (b), A is --CH.sub.2--,
B is --O--, m is 1.
[0086] Reaction of an aldehyde of Formula (12) with a half acid of
Formula (8) by the Knoevenagel procedure described above affords an
acrylate of Formula (19). 19
[0087] Deprotection of an ether of Formula (19) using ethanolic
hydrogen chloride affords a phenol of Formula (20). 20
[0088] Alkylation of a phenol of Formula (20) using an allyl
chioroacetate of Formula (21)
ClCH.sub.2CO.sub.2Allyl (21)
[0089] in a solvent such as dimethylformamide using a base such as
anhydrous potassium carbonate provides a mixed ester of Formula
(22). 21
[0090] Selective cleavage of an allyl ester of Formula (22) using
triethylsilane in the presence of a catalyst such as
triphenylphosphine palladium (0) in a solvent such as
dichloromethane provides a mono acid of Formula (23). 22
[0091] Coupling a mono acid of formula (23) with a sulfonamide of
Formula (24)
R.sub.9SO.sub.2NH.sub.2 (24)
[0092] in the presence of a catalyst such as
4-dimethylaminopyridine and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in a
solvent such as dichloromethane at reflux affords a sulfonamide of
Formula of (25). 23
[0093] Saponification of an ester of Formula (25) using aqueous
sodium hydroxide in a solvent such as ethanol affords, after
acidification with aqueous hydrochloric acid, an acid of Formula
(I), wherein R.sub.2 is OCH.sub.2CO.sub.2NHSO.sub.2R.sub.9, A is
--CH.sub.2--, B is -O--, R.sub.4 is hydrogen, and P is
CO.sub.2H.
[0094] Alternatively, a phenol of Formula (20) may by alkylated
with chloroacetonitrile in a solvent such as dimethylformamide to
produce a compound of Formula (26). 24
[0095] Reaction of a nitrile of Formula (26) with sodium azide in
the presence of trimethyltin chloride in a solvent such as toluene
at elevated temperature affords a tetrazole of Formula (27). 25
[0096] Saponification of an ester of Formula (27) using aqueous
sodium hydroxide in a solvent such as ethanol affords, after
acidification with aqueous hydrochloric acid, an acid of Formula
(I), wherein R.sub.2 is OCH.sub.2(tetrazol-5-yl), A is
--CH.sub.2--, B is --O--, R is hydrogen, and P is CO.sub.2H.
[0097] Alternatively, a phenol of Formula (20) may also be
alkylated with an alkyl halide of Formula (28), where X is I, Br,
or Cl;
R.sub.7(CH.sub.2).sub.nX (28)
[0098] to provide an ether of Formula (29). 26
[0099] Saponification of an ester of Formula (29) using aqueous
sodium hydroxide in a solvent such as ethanol affords, after
acidification with aqueous hydrochloric acid, an acid of Formula
(1), wherein R.sub.2 is O(CH.sub.2).sub.nR.sub.7, A is
--CH.sub.2--, B is --O--, R.sub.4 is hydrogen, P is CO.sub.2H.
[0100] In order to use a compound of the Formula (I) or a
pharmaceutically acceptable salt thereof for the treatment of
humans and other mammals it is normally formulated in accordance
with standard pharmaceutical practice as a pharmaceutical
composition.
[0101] Compounds of Formula (I) and their pharmaceutically
acceptable salts may be administered in a standard manner for the
treatment of the indicated diseases, for example orally,
parenterally, sub-lingually, transdermally, rectally, via
inhalation or via buccal administration.
[0102] Compounds of Formula (I) and their pharmaceutically
acceptable salts which are active when given orally can be
formulated as syrups, tablets, capsules and lozenges. A syrup
formulation will generally consist of a suspension or solution of
the compound or salt in a liquid carrier for example, ethanol,
peanut oil, olive oil, glycerine or water with a flavouring or
colouring agent. Where the composition is in the form of a tablet,
any pharmaceutical carrier routinely used for preparing solid
formulations may be used. Examples of such carriers include
magnesium stearate, terra alba, talc, gelatin, agar, pectin,
acacia, stearic acid, starch, lactose and sucrose. Where the
composition is in the form of a capsule, any routine encapsulation
is suitable, for example using the aforementioned carriers in a
hard gelatin capsule shell. Where the composition is in the form of
a soft gelatin shell capsule any pharmaceutical carrier routinely
used for preparing dispersions or suspensions may be considered,
for example aqueous gums, celluloses, silicates or oils and are
incorporated in a soft gelatin capsule shell.
[0103] Typical parenteral compositions consist of a solution or
suspension of the compound or salt in a sterile aqueous or
non-aqueous carrier optionally containing a parenterally acceptable
oil, for example polyethylene glycol, polyvinylpyrrolidone,
lecithin, arachis oil, or sesame oil.
[0104] Typical compositions for inhalation are in the form of a
solution, suspension or emulsion that may be administered as a dry
powder or in the form of an aerosol using a conventional propellant
such as dichlorodifluoromethane or trichlorofluoromethane.
[0105] A typical suppository formulation comprises a compound of
Formula (1) or a pharmaceutically acceptable salt thereof which is
active when administered in this way, with a binding and/or
lubricating agent, for example polymeric glycols, gelatins,
cocoa-butter or other low melting vegetable waxes or fats or their
synthetic analogues.
[0106] Typical transdermal formulations comprise a conventional
aqueous or non-aqueous vehicle, for example a cream, ointment,
lotion or paste or are in the form of a medicated plaster, patch or
membrane.
[0107] Preferably the composition is in unit dosage form, for
example a tablet, capsule or metered aerosol dose, so that the
patient may administer to themselves a single dose.
[0108] Each dosage unit for oral administration contains suitably
from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg,
and each dosage unit for parenteral administration contains
suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof calculated as the free
acid. Each dosage unit for intranasal administration contains
suitably 1-400 mg and preferably 10 to 200 mg per person. A topical
formulation contains suitably 0.01 to 1.0% of a compound of Formula
(I).
[0109] The daily dosage regimen for oral administration is suitably
about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof calculated as the free
acid. The daily dosage regimen for parenteral administration is
suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the
Formula (I) or a pharmaceutically acceptable salt thereof
calculated as the free acid. The daily dosage regimen for
intranasal administration and oral inhalation is suitably about 10
to about 500 mg/person. The active ingredient may be administered
from 1 to 6 times a day, sufficient to exhibit the desired
activity.
[0110] No unacceptable toxicological effects are expected when
compounds of the invention are administered in accordance with the
present invention.
[0111] The biological activity of the compounds of Formula (I) are
demonstrated by the following tests:
[0112] I. Binding Assay
[0113] A) Membrane Preparation
[0114] Rat cerebellum or kidney cortex were rapidly dissected and
frozen immediately in liquid nitrogen or used fresh. The tissues,
1-2 g for cerebellum or 3-5 g for kidney cortex, were homogenized
in 15 mls of buffer containing 20 mM Tris HCl and 5 mM EDTA, pH 7.5
at 4.degree. C. using a motor-driven homogenizer. The homogenates
were filtered through cheesecloth and centrifuged at 20,000.times.
g for 10 minutes at 4.degree. C. The supernatant was removed and
centrifuged at 40,000.times. g for 30 minutes at 4.degree. C. The
resulting pellet was resuspended in a small volume of buffer
containing 50 mM Tris, 10 mM MgCl.sub.2, pH 7.5; aliquotted with
small vials and frozen in liquid nitrogen. The membranes were
diluted to give 1 and 5 mg of protein for each tube for cerebellum
and kidney cortex in the binding assay.
[0115] Freshly isolated rat mesenteric artery and collateral
vascular bed were washed in ice cold saline (on ice) and lymph
nodes were removed from along the major vessel. Then, the tissue
was homogenized using a polytron in buffer containing 20 mM Tris
and 5 mM EDTA, pH 7.5 at 4.degree. C. in 15 ml volume for .about.6
gm of mesenteric artery bed. The homogenate was strained through
cheesecloth and centrifuged at 2,000.times. g for 10 min. at
4.degree. C. The supernatant was removed and centrifuged at
40,000.times. g for 30 min. at 4.degree. C. The resulting pellet
was resuspended as explained above for cerebellum and kidney
cortex. Approximately 10 mg of membrane protein was used for each
tube in binding experiments.
[0116] B) [.sup.125I]ET-1 Binding Protocol
[0117] [.sup.125I]ET-1 binding to membranes from rat cerebellum
(2-5 mg protein/assay tube) or kidney cortex (3-8 mg protein/assay
tube) were measured after 60 minutes incubation at 30.degree. C. in
50 mM Tris HC1, 10 nM MgCl.sub.2, 0.05% BSA, pH 7.5 buffer in a
total volume of 100 ml. Membrane protein was added to tubes
containing either buffer or indicated concentration of compounds.
[.sup.125I]ET-1 (2200 Ci/mmol) was diluted in the same buffer
containing BSA to give a final concentration of 0.2-0.5 nM ET-1.
Total and nonspecific binding were measured in the absence and
presence of 100 nM unlabelled ET-1. After the incubation, the
reactions were stopped with 3.0 ml cold buffer containing 50 mM
Tris and 10 mM MgCl.sub.2, pH 7.5. Membrane bound radioactivity was
separated from free ligand by filtering through Whatman GF/C filter
paper and washing the filters 5 times with 3 ml of cold buffer
using a Brandel cell harvester. Filter papers were counted in a
gamma counter with an efficiency of 75%.
[0118] II. In Vitro Vascular Smooth Muscle Activity
[0119] Rat aorta are cleaned of connective tissue and adherent fat,
and cut into ring segments approximately 3 to 4 mm in length.
Vascular rings are suspended in organ bath chambers (10 ml)
containing Krebs-bicarbonate solution of the following composition
(millimolar): NaCl, 112.0; KCl, 4.7; KH.sub.2PO.sub.4, 1.2;
MgSO.sub.4, 1.2; CaCl.sub.2, 2.5; NaHCO.sub.3, 25.0; and dextrose,
11.0. Tissue bath solutions are maintained at 37.degree. C. and
aerated continuously with 95% O.sub.2/5% CO.sub.2. Resting tensions
of aorta are maintained at 1 g and allowed to equilibrate for 2
hrs., during which time the bathing solution is changed every 15 to
20 min. Isometric tensions are recorded on Beckman R-611 dynographs
with Grass FT03 force-displacement transducer. Cumulative
concentration-response curves to ET-1 or other contractile agonists
are constructed by the method of step-wise addition of the agonist.
ET-1 concentrations are increased only after the previous
concentration produces a steady-state contractile response. Only
one concentration-response curve to ET-1 is generated in each
tissue. ET receptor antagonists are added to paired tissues 30 min
prior to the initiation of the concentration-response to
contractile agonists.
[0120] ET-1 induced vascular contractions are expressed as a
percentage of the response elicited by 60 mM KCl for each
individual tissue which is determrined at the beginning of each
experiment. Data are expressed as the mean .+-.S.E.M. Dissociation
constants (K.sub.b) of competitive antagonists were determined by
the standard method of Arunlakshana and Schild.
[0121] The following examples are illustrative and are not limiting
of the compounds of this invention.
EXAMPLE I
(E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)]carboxamido-4-methoxyphenyl]-1H-im-
idazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoic
acid dipotassium
[0122] a) 2,4-Dimethoxynitrobenzene
[0123] To a solution of sodium methoxide in methanol (freshly
prepared by adding 50.0 g (2.17 mol) of sodium, in portions, to 1.5
l of methanol at 0.degree. C.) was added 2,4-dichloro-nitrobenzene
(95.0 g, 0.495 mol) in methanol (100 ml). After refluxing for 3
days, the reaction mixture was cooled in an ice bath and filtered,
the precipitate was washed with water and dried (Na.sub.2SO.sub.4).
The title compound was collected as a yellow solid (83.0 g,
91%).
[0124] b) 2-Hydroxy-4-methoxynitrobenzene
[0125] To a solution of dimethoxynitrobenzene (30.0 g, 0.163 mol)
in 99% methanesulfonic acid (300 ml) was added dl-methionine (31.8
g, 0.212 mol) and the mixture was stirred at rt for 24 h. The
solution was poured onto ice and stirred with water (1.5 l). The
precipitate was filtered and washed with water. The title compound
was collected as a yellow solid (23.1 g, 84%).
[0126] c) 2-Methoxymethoxy-4-methoxynitrobenzene
[0127] To a solution of hydroxynitrobenzene (21.2 g, 0.125 mol) in
DMF (250 ml) was added sodium hydride (4.5 g, 0.188 mol) at
0.degree. C. under argon. The mixture was allowed to stir at
0.degree. C. for 1 h, then bromomethyl methylether (22 ml, 0.150
mol) was added. After stirring for 18 h at rt the reaction was
quenched with water. The mixture was extracted with ethyl acetate
(3.times.30 ml) and the combined organic extracts were washed with
brine and dried (Na.sub.2SO.sub.4). Removal of the solvent under
reduce pressure gave the title compound as a brown oil (23.4 g,
88%).
[0128] d) 2-Methoxymethoxy-4-methoxy aniline
[0129] To a solution of nitrobenzene (10.0 g, 0.047 mol) in ethanol
(50 ml) was added 10% Pd/C (1.0 g) and the mixture was shaken under
hydrogen atmosphere at 55 mm Hg for 24 h at rt. The mixture was
filtered through a pad of Celite and the filtrate was dried
(Na.sub.2SO.sub.4). Removal of the solvent afforded the title
compound as a brown oil (8.2 g, 95%).
[0130] e) 1-Methoxypentaimidate Hydrochloride
[0131] To a solution of valeronitrile (72.3 g, 0.872 mol) in
methanol (75 ml) was bubbled through gaseous HCl until saturation.
The solution was then placed in the freezer for three days. The
precipitate was filtered and was rinsed several times with ether.
The title compound was collected as a white solid (130.0 g,
99%).
[0132] f) 1-Methoxypentaimidate
[0133] To a suspension of the HCl salt (16.5 g, 0.108 mol), in
anhydrous ether (50 ml) was added triethylamine (15.5 ml, 0.110
mol). The mixture stirred at rt for 18 h under argon and then the
precipitate was filtered. The filtrate was concentrated to 80%
dryness and the crude product was used in the next reaction without
further purification.
[0134] g) N-(2-Methoxymethoxy-4-methoxyphenyl)-pentanamidine
[0135] To a solution of 1-methoxypentaimidate (11.3 g, 0.109 mol)
in dichloromethane (20 ml) was added freshly prepared
2-methoxymethoxy-4-methoxy aniline (10.0 g, 0.055 mol) of Example 1
(d) and the mixture was stirred at reflux for 3 days. After
removing the solvent flash chromatography of the residue (silica
gel, 5% methanol/dichloromethane) afforded the title compound as a
dark solid (11.7 g, 85%).
[0136] h)
2-Butyl-1-(2-methoxymethoxy-4-methoxyphenyl)-1H-imidazol-5-carbo-
xaldehyde
[0137] To a solution of
N-(2-Methoxymethoxy-4-methoxyphenyl)-pentanamidine (5.10 g, 0.019
mol) in iso-propanol (50 ml) was added triethylamine (3.20 ml,
0.0230 mol), acetic acid (1.4 mnl, 0.025 mol) and
2-bromo-1,3-dicarboxaldehyde propane (3.20 g, 0.0211 mol),
respectively. The mixture was stirred at reflux for 5 h and then
cooled to room temperature. After filtration and concentration, The
crude residue was dissolved in ethyl acetate and washed with 10%
sodium bicarbonate solution, water, dried (Na.sub.2SO.sub.4). After
removing the solvent under reduced pressure, flash chromatography
of the residue (silica gel, 25% ethyl acetate/hexane) afforded the
title compound as a dark yellow oil (3.85 g, 63%).
[0138] i) 1-Methoxy-3,4-methylenedioxybenzene
[0139] To a solution of sesamol (10.0 g, 0.072 mol) in DMF (50 ml)
was added sodium hydride (2.08 g, 0.087 mol) at rt under argon.
After stirring for 1 h the mixture was treated with lodomethane
(13.5 ml, 0.216 mol) and stirred for another 18 h. Upon the removal
of the solvent the residue was extracted with ethyl acetate and
washed with water, dried (Na.sub.2SO.sub.4) and concentrated to
afford the title compound as a dark brown oil (10.5 g, 96%).
[0140] j) 2-Methoxy-4,5-methylenedioxy Benzaldehyde
[0141] To a solution of phosphorous oxychloride (3.0 mnl, 0.033
mol) in DlNvIF (10 ml) was added a solution of
1-methoxy-3,4-methylenedioxybenzen- e (2.0 g, 0.013 mol) in DMF (2
ml) at 0.degree. C. After stirring at 60.degree. C. for 18 h the
mixture was cooled to 0.degree. C. and then poured into water (500
ml). The precipitate was filtered and dried. The title compound was
collected as a yellow solid (2.20 g, 92%).
[0142] k) Diethyl
2-(4,5-methylenedioxy-1-methoxybenzyliden)-maionate
[0143] A solution of the 2-methoxy-4,5-methylenedioxy benzaldehyde
(16.0 g, 0.089 mol), diethyl malonate (15.0 ml, 0.090 mol),
piperidine (4.4 ml, 0.044 mol) and acetic acid (2.5 ml, 0.045 mol)
in benzene (75 ml) stirred at reflux, equipped with a Dean-Stark
apparatus, for 24 h. Upon removal of the solvent the crude residue
was extracted with ethyl acetate and washed with 10% sodium
carbonate solution, water, dried (Na.sub.2SO.sub.4). After removing
the solvent, flash chromatography of the residue (silica gel, 25%
ethyl acetate/hexane) provided the title compound as a yellow solid
(26.0 g, 91%).
[0144] l) Diethyl
2-(4,5-methylenedioxy-1-methoxybenzyl)-malonate
[0145] To a solution of the diethyl
2-(4,5-methylenedioxy-1-methoxybenylid- ene)-malonate (23.4 g,
0.073 mol) in ethanol (100 ml) was added sodium borohydride (2.8 g,
0.073 mol) and the mixture was stirred at rt for 5 h. The reaction
was quenched with water and extracted with ethyl acetate
(3.times.200 mL). The combined organic extracts were dried
(Na.sub.2SO.sub.4) and evaporated to afford the title compound as
an oil (20.3 g, 86%).
[0146] m) Ethyl Hydrogen
2-(4,5-methylenedioxy-1-methoxybenyl)-malonate
[0147] To a solution of the diethyl
2-(4,5-methylenedioxy-1-methoxybenyl)-- malonate (20.0 g, 0.066
mol) of in ethanol (50 ml) was added a solution of potassium
hydroxide (3.5 g, 0.066 mol) in water (25 ml). The solution stirred
at reflux for 6 h. After concentrating the aqueous layer was washed
with ether and acidified with concentrated HCl to pH 1 and
extracted with ethyl acetate. The organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated to afford the title compound as
a yellow solid (17.3 g, 89%).
[0148] n)
Ethyl-(E)-3-[2-butyl-1-(2-(methoxymethoxy).sub.4-methoxyphenyl)--
1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenc-
ate
[0149] A solution of
1-(2-methoxymethoxy-4-methoxyphenyl)-1H-imidazol-5-ca- rboxaldehyde
(1.00 g, 2.976 mmol) of Example 3(b), ethyl hydrogen
2-(4,5-methylenedioxy-1-methoxybenzyl)-malonate (2.64 g, 8.930
mmol), piperidine(0.15 ml, 1.488 mmol) and acetic acid (0.085 ml,
1.488 mmol) in benzene (50 ml) was equipped with a Dean-Stark
apparatus, and stirred at reflux for 24 h. The solvent was removed
and the crude residue was extracted with ethyl acetate and washed
with 10% sodium carbonate solution, water, dried
(Na.sub.2SO.sub.4). After removing the solvent flash chromatography
of the residue (silica gel, 50% ethyl acetate/hexane) yielded the
title compound as a brown oil (1.03 g, 63%). Anal.
(C.sub.30H.sub.36N.sub.2O.sub.8) calcd: C, 65.18; H, 6.58; N, 5.07.
found: C, 64.85; H, 6.20; N, 4.93.
[0150] o)
Ethyl-(E)-3-[2-butyl-1-(2-hydroxy-4-methoxyphenyl)]-1H-imidazol--
5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
[0151] To a solution of the
ethyl-(E)-3-[2-butyl-1-(2-(methoxymethoxy)4-me-
thoxyphenyl)]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmet-
hyl]-2-propenoate (1.00 g, 1.811 mmol) in ethanol (25 ml) was added
a catalytic amount of concentrated HCl. After stirring at reflux
for 5 h the solvent was removed and the residue was extracted with
ethyl acetate and washed with sodium bicarbonate (satd.), dried
(Na.sub.2SO.sub.4). After removing the solvent flash chromatography
of the residue (silica gel, 50% ethyl acetateihexane) gave the
title compound as a brown oil (0.856 g, 93%). Anal.
(C.sub.28H.sub.32N.sub.2O.sub.7) calcd: C, 66.10; H, 6.36; N, 5.51.
found: C, 65.92; H, 6.01; N, 5.12.
[0152] p)
Ethyl-(E)-3-[2-butyl-1-(2-allylcarbomethoxy).sub.4-methoxyphenyl-
]-1H-imidazol-5-yl-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propen-
oate
[0153] To a solution of the
ethyl-(E)-3-[2-butyl-1-(2-hydroxy-4-methoxyphe-
nyl)]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-p-
ropenoate (0.38 g, 0.776 mmol) in DMF (10 ml) was added sodium
hydride (0.024 g, 0.996 mmol) and stirred at rt for 1 h under
argon. Allyl chloroacetate (0.110 ml, 0.919 mmol) was added to the
mixture and was allowed to stir for 18 h. The reaction was quenched
with water and extracted with ethyl acetate. The organic extracts
were washed with water, brine and dried (Na.sub.2SO.sub.4). After
removing the solvent flash chromatography of the residue (silica
gel, 50% ethyl acetate/hexane) afforded the title compound as a
brown oil (0.426 g, 92%): MS(ESI) mr/e 607.2 [M+H].sup.+.
[0154] q)
Ethyl-(E)-3-[2-butyl-1-(2-carbomethoxy).sub.4-methoxyphenyl]-1H--
imidazol-5-yl-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
[0155] To a solution of
ethyl-(E)-3-[2-butyl-1-(2-allylcarbomethoxy).sub.4-
-methoxy-phenyl]-1H-imidazol-5-yl-2-[(2-methoxy-4,5-methylenedioxy)phenylm-
ethyl]-2-propenoate (0.47 g, 0.791 mmol) in dichloromethane (10 ml)
was added triethylsilane (0.70 ml, 4.384 mmol) and
tetrakis(triphenylphosphin- e)palladium(0) (0.20 g, 0.175 mmol),
respectively. After refluxing for 3 h, the reaction was quenched
with water. The mixture was extracted with ethyl acetate
(3.times.15 mL). The combined organic extracts were washed with
brine and dried (Na.sub.2SO.sub.4). After removing the solvent,
flash chromatography of the residue (silica gel, ethyl acetate)
gave the title compound as a brown solid (0.400 g, 91%): Anal.
(C.sub.30H.sub.34N.sub.2O.sub.9) calcd: C, 63.58; H, 6.06; N, 4.94.
found: C, 63.21; H, 5.87; N, 4.63.
[0156] r)
Ethyl-(E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)]carboxamido-4-meth-
oxyphenyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphcnyl)methyl-
]-2-propenoate
[0157] A solution of
ethyl-(E)-3-[2-butyl-1-(2-carbomethoxy)-4-methoxyphen-
yl]-1H-imidazol-5-yl-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-prop-
enoate (0.210 g, 0.379 mmol),
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimi- de hydrochloride
(0.087 g, 0.455 mmol), 4-dimethyl-aminopyridine (0.117 g, 0.955
mmol) and benzenesulfonamide (0.065 g, 0.417 mmol) in
dichloromethane (25 ml) was allowed to stir at reflux for 5 h. The
reaction was quenched with water and *i extracted with ethyl
acetate. The organic extract was washed with brine and dried
(Na.sub.2SO.sub.4). After removing the solvent, flash
chromatography of the residue (silica gel, ethyl acetate) afforded
the title compound as a yellow oil (0.192 g, 72%): Anal.
(C.sub.36H.sub.39N.sub.3O.sub.10S) calcd: C, 61.25; H, 5.59; N,
5.96. found: C, 60.95; H, 5.25; N, 5.67.
[0158] s)
(E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)lcarboxamido-4-methoxyphe-
nyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-pr-
opnoic Acid
[0159] To a solution of
ethyl-(E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)]carb-
oxamido-4-methoxyphenyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenediox-
y)phenylmethyl]-2-propenoate (0.150 g, 0.213 mmol) in methanol (10
ml) was added a solution of potassium hydroxide (0.020 g, 0.319
mmol) in water (4 ml). The reaction was allowed to stir at reflux
for 6 h. The organic solvent was removed and the aqueous layer was
washed with ethyl acetate. The aqueous layer was acidified with
concentrated HCl and extracted with ethyl acetate. The organic
extract was washed with brine and dried (Na.sub.2SO.sub.4). After
removing the solvent, crystallization of the residue from methanol
afforded the title compound as a yellow solid (0.130 g, 91%): m.p.
155.degree. C.; Anal. (C.sub.34H.sub.35N.sub.3O.sub.- 9S) calcd: C,
60.25; H, 5.22; N, 6.20. found: C, 60.11; H, 5.01; N, 5.92.
[0160] t)
(E)-3-[2-Butyl-1-[2-[N-(phenylsulfonyl)]carboxamido-4-methoxyphe-
nyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-pr-
openic Acid Dipotassium
[0161] A solution of the
(E)-3-[2-butyl-1-[2-[N-(phenylsulfonyl)]carboxamr-
ido-4-methoxy-phenyl]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)p-
henylmethyl]-2-propenoic acid (0.090 g, 0.133 mmol) in 95% ethanol
(20 ml) was titrated with a solution of potassium hydroxide (0.5 M)
in 95% ethanol until pH 7.9 was obtained. The solvent was removed
and dried in vacuum to afford the title compound as a light yellow
solid (0.100 g, 99%): .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
7.72 (d, J=10 Hz, 2H), 7.39 (m, 3H), 7.05 (d, 1H), 6.89 (s, 1H),
6.72 (s, 1H), 6.55 (d, 2H), 6.42 (s, 1H), 6.35 (s, 1H), 5.92 (s,
2H), 4.26 (dd, J=10 Hz, 20 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H),
3.65 (d, 2H), 1.48 (p, 2H), 1.21 (sextet, 2H), 0.80 (t, 3H);
MS(ESI) m/e 678.2 [M+H].sup.+(free acid).
EXAMPLE 2
(E)-3-[2-Butyl-1-(2-benzyloxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(2-met-
hoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid
[0162] a)
Ethyl-(E)-3-[2-Butyl-1-(2-benzyloxy-4-methoxy)phenyl-1H-imidazol-
-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
[0163] To a solution of
ethyl-(E)-3-[2-Butyl-1-(2-hydroxy-4-methoxy)phenyl-
-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propen-
oate (0.176 g, 0.334 mmol) in DMF (8 ml) was added sodium hydride
(0.027 g, 0.675 mmol) at 0.degree. C. under argon, followed by
benzyl bromide (0.048 ml, 0.401 mmol). After stirring for 1 h at rt
the reaction was quenched with water. The mixture was extracted
with ethyl acetate and the combined organic extracts were washed
with brine and dried (Na.sub.2SO.sub.4). After removing the
solvent, flash chromatography of the residue (silica gel, 1:1
hexane:ethyl acetate) afforded the title compound as an oil (0.044
g, 72%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34-7.13 (m,
7H), 7.10 (d, 1H), 6.65 (d, 1H), 6.60 (dd, 1H), 6.55 (s, 1H), 6.43
(s, 1H), 5.82 (s, 3H), 5.05 (s, 2H), 4.13 (q, 2H), 3.85 (s, 3H),
3.82 (s, 2H), 3.81 (s, 2H), 2.48 (m, 2H), 1.57 (m, 2H), 1.21
(sextet, 2H), 1.15 (t, 3H), 0.77 (t, 3H).
[0164] b)
(E)-3-[2-Butyl-1-(2-benzyloxy-4-methoxy)phenyl-1H-imidazol-5-yl]-
-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid
[0165] To a solution of
ethyl-(E)-3-[2-Butyl-1-(2-benzyloxy-4-methoxy)phen-
yl-1H-imidazol-5-yl]-2-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-prope-
noate (0.140 g, 0.234 mol) in methanol (2 mL) was added 0.5 mL of
10% sodium hydroxide. The reaction was allowed to stir at reflux
for 6 h. The organic solvent was removed and the aqueous layer was
acidified with 6N HCl and extracted with ethyl acetate. The organic
extract was washed with brine and dried (Na.sub.2SO.sub.4). After
removing the solvent, flash chromatography of the residue (silica
gel, 2:1 ethyl acetate:hexane) afforded the title compound as an
off white solid (0.100 g, 75%): MS (ESI) m/e 571 [M+H].sup.+; mp:
215-216.degree. C. (dec.); Anal.
(C.sub.33H.sub.34N.sub.2O.sub.7.0.5H.sub.2O) calcd. C, 68.38; H,
6.09; N, 4.83: found: C, 68.31; H1, 6.00; N, 4.78.
EXAMPLE 3
(E)-3-[2-Butyl-1-[2-(2-picolyloxy)-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(-
2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic Acid
[0166] a)
Ethyl-(E)-3-[2-Butyl-1-[2-(2-picolyl)oxy-4-methoxy]phenyl-1H-imi-
dazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
[0167] To a solution of
ethyl-(E)-3-[2-Butyl-1-(2-hydroxy-4-methoxy)phenyl-
-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propen-
oate (0.100 g, 0.197 mmol) in DMF (5 mL) was added sodium hydride
(0.024 g, 0.60 mmol) at 0.degree. C. under argon, followed by
2-picolyl chloride hydrochloride (0.042 g, 0.256 mmol). After
stirring for 16 h at rt the reaction was quenched with water. The
mixture was extracted with ethyl acetate and the combined organic
extracts were washed with brine and dried (Na.sub.2SO.sub.4). After
removing the solvent, flash chromatography of the residue (silica
gel, 1:2 hexane:ethyl acetate) afforded the title compound as an
oil (0.035 g, 30%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.52
(d, 1H), 7.61 (t, 1H), 7.24-7.14 (m, 4H), 7.13 (d, 1H), 7.00 (d,
1H), 6.68 (d, 1H), 6.64 (dd, 1H), 6.55 (s, 2H), 6.43 (s, 2H), 5.82
(s, 2H), 5.14 (s, 2H), 4.10 (q, 2H), 3.87 (s, 3H), 3.84 (s, 5H),
2.45 (m, 2H), 1.57 (m, 2H), 1.22 (m, 2H), 1.14 (t, 3H), 0.77 (t,
3H).
[0168] b)
(E)-3-[2-Butyl-1-[2-(2-picolyl)oxy-4-methoxy]phenyl-1H-imidazol--
5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0169] To a solution of ethyl
(E)-3-[2-Butyl-1-[2-(2-picolyl)oxy-4-methoxy-
]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-
-propenoate (0.035 g, 0.058 mmol) in methanol (2 mL) was added 1 ml
of 10% sodium hydroxide. The reaction was allowed to stir at reflux
for 6 h. The organic solvent was removed under reduced pressure and
the aqueous layer was acidified with aqueous acetic acid and
extracted with ethyl acetate. The organic extract was washed with
brine and dried (Na.sub.2SO.sub.4). Removal the solvent under
reduce pressure afforded the title compound as an oil (0.030 g,
91%): MS (ESI) m/e 572 [M+H].sup.+; mp: 220-222.degree. C. (dec.);
Anal. (C.sub.32H.sub.33N.sub.3O.sub.7.H.sub.2O) calcd. C, 65.18; H,
5.98; N, 7.13: found C, 65.25, H, 5.93; N, 6.80.
EXAMPLE 4
(E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-methoxy]phenyl-1H-imidazol-5--
yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid
[0170] a)
Ethyl-(E)--3-[2-Butyl-1-(2-cyanomethoxy-4-methoxy)phenyl-1H-imid-
azol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
[0171] To a solution of
ethyl-(E)-3-[2-Butyl-1-[2-hydroxy-4-methoxy]phenyl-
-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propen-
oate (0.200 g, 0.403 mmol) in DMF (5 mL) was added sodium hydride
(0.012 g, 0.484 mmol) at 0.degree. C. under argon. The mixture was
allowed to stir at room temperature for 1 h, then to it was added
bromoacetonitrile (0.031 mL, 0.443 mmol) was added. After stirring
for 24 h at rt the reaction was quenched with water. The mixture
was extracted with ethyl acetate and the combined organic extracts
were washed with brine and dried (Na.sub.2SO.sub.4). After removing
the solvent, flash chromatography of the residue (silica gel, 1:1
hexane:ethyl acetate) afforded the title compound as a brown oil
(0.198 g, 92%): .sup.1H NMR (250 MHz, CDCl.sub.3) .delta. 6.55 (s,
1H), 6.44 (s, 1H), 5.85 (s, 2H), 4.68 (s, 2H), 4.11 (q, 2H), 3.91
(s, 3H), 3.84 (s, 2H), 3.82 (s, 3H), 2.42 (m, 2H), 1.58 (quintet,
2H), 1.26 (m, 2H), 1.17 (t, 3H), 0.83 (t, 3H); MS (ESI) m/e 536.2
[M+H].sup.+.
[0172] b)
Ethyl-(E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-methoxy]pheny-
l-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-prope-
noate
[0173] To a solution of sodium azide (0.061 g, 0.935 mmol) and
trimethyltin chloride (0.150 g, 0.748 mmol) in toluene (10 mL) was
added
ethy-(E)-3-[2-Butyl-1-(2-cyanomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]--
2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate at room
temperature. The mixture was stirred at reflux for 24 h. The
reaction was cooled to room temperature then treated with a
solution of methanolic 1N HCl (2 mL). The mixture was extracted
with ethyl acetate and the combined organic extract were washed
with brine and dried (Na.sub.2SO.sub.4). After removing the solvent
under reduced pressure, flash chromatography of the residue (silica
gel, ethyl acetate) afforded the title compound as a brown solid
(0.080 g, 72%): .sup.1H NMR (250 MHz, CDCl.sub.3) .delta. 7.17-7.07
(m, 3H), 6.97 (d, 1H), 6.72 (dd, 1H), 6.66 (s, 1H), 6.35 (s, 1H),
5.83 (s, 2H), 5.32 (dd, 2H), 4.10 (q, 2H), 3.92 (s, 3H), 3.83 (s,
3H), 3.74 (s, 2H), 2.36 (mm, 2H), 1.44 (quintet, 2H), 1.16 (m, 5H),
0.75 (t, 3H); MS (ESI) m/e 591.2 [M+H].sup.+;mp: 140-144.degree.
C.
[0174] c)
(E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-methoxy]phenyl-1H-i-
rmidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0175] To a solution of
ethyl-(E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-
-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)m-
ethyl]-2-propenoate (0.100 g, 0.169 mmol) in methanol (5 mL) was
added 3 ml of IN sodium hydroxide. The reaction mixture was allowed
to stir at reflux for 2 h. The organic solvent was removed and the
aqueous layer was acidified with concentrated HCl and extracted
with ethyl acetate. The organic extract was washed with brine and
dried (Na.sub.2SO.sub.4). Removal of the solvent under reduce
pressure afforded the title compound as a brown solid (0.078 g,
82%): MS (ESI) m/e 563.2 [M+H].sup.+; mp: 208-210.degree. C.; Anal.
(C.sub.28H.sub.30N.sub.6O.sub.7) calcd. C, 59.72; H, 5.38; N,
14.93: found C, 59.38; H, 5.26; N, 14.72.
EXAMPLE 5
(E)-3-[2-Butyl-1-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl
1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propen-
oic Acid
[0176] a)
Ethyl-(E)-3-[2-Butyl-1-[2-(2-carboxyphenyl)methoxy-4-methoxy]phe-
nyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-pro-
penoate
[0177] To a solution of
ethyl-(E)-3-[2-Butyl-1-(2-hydroxy-4-methoxy)phenyl-
-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propen-
oate (0.100 g, 0.197 mmol) in DMF (5 mL) was added sodium hydride
(0.024 g, 0.60 mmol) at 0.degree. C. under argon, followed by
methyl o-bromomethyl benzoate (0.042 g, 0.256 mmol). After stirring
for 2 h at 0.degree. C. the reaction was quenched with water. The
mixture was extracted with ethyl acetate and the combined organic
extracts were washed with brine and dried (Na.sub.2SO.sub.4). After
removing the solvent, flash chromatography of the residue (silica
gel, 1:2 hexane:ethyl acetate) afforded the title compound as an
oil (0.035 g, 30%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.52
(d, 1H), 7.61 (t, 1H), 7.24-7.14 (m, 4H), 7.13 (d, 1H), 7.00 (d,
1H), 6.68 (d, 1H), 6.64 (dd, 1H), 6.55 (s, 2H), 6.43 (s, 2H), 5.82
(s, 2H), 5.14 (s, 2H), 4.10 (q, 2H), 3.87 (s, 3H), 3.84 (s, 5H),
2.45 (m, 2H), 1.57 (m, 2H), 1.22 (m, 2H), 1.14 (t, 3H), 0.77 (t,
3I-1).
[0178] b)
(E)-3-[2-Butyl-1-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-
-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0179] To a solution of ethyl
(E)-3-[2-Butyl-1-[2-(2-carboxyphenyl)methoxy-
-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl-
)methyl)-2-propenoate (0.035 g, 0.058 mmol) in methanol (2 mL) was
added 1 ml of 10% sodium hydroxide. The reaction was allowed to
stir at reflux for 6 h. The organic solvent was removed under
reduced pressure and the aqueous layer was acidified with aqueous
acetic acid and extracted with ethyl acetate. The organic extract
was washed with brine and dried (Na.sub.2SO.sub.4). Removal the
solvent under reduce pressure afforded the title compound as an oil
(0.030 g, 91%): MS (ESI) m/e 572 [M+H].sup.+; mp: 220-222.degree.
C. (dec.); Anal. (C.sub.32H.sub.33N.sub.- 3O.sub.7-H.sub.2O) calcd.
C, 65.18; H, 5.98; N, 7.13. found C, 65.25, H, 5.93; N, 6.80.
EXAMPLE 6
E-3-[2-Butyl-1-[2-(2-ethyl-2H-tetrazol-5-yl)methoxy-4-methoxy]phenyl-1H-im-
idazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid
[0180] a)
Ethyl-(E)-3-[2-Butyl-1-[2-(2-ethyl-2H-tetrazol-5-yl)methoxy-4-me-
thoxy]phenyl-1H-1mdazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methy-
l]-2-propenoate
[0181] To a solution of
ethyl-(E)-3-[2-Butyl-1-[2-(tetrazol-5-yl)methoxy-4-
-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)m-
ethyl]-2-propenoate (0.100 g, 17.30 mmol) in DMF (10 mL) was added
sodium hydride(5 mg, 0.225 mmol) followed by ethyl iodide (16
.mu.L, 0.20 mmol). The reaction mixture was allowed to stir at room
temperature for 18 h and quenched with water. The mixture was
extracted with 1:1 hexane/ethyl acetate and the organic extract was
washed with brine and dried (Na.sub.2SO.sub.4). After removing the
solvent, column chromatography of the residue with 1:1 hexane/ethyl
acetate afforded the title compound as an oil (92 mg, 86%): .sup.1H
NMR (250 MHz, CDCl.sub.3) .delta. 0.80 (t, 3H), 1.15 (t, 3H), 1.6
(m, 2H), 1.65 (t, 3H), 2.40 (m, 2H), 3.82 (s, 3H), 3.83 (d, 2H),
3.88 (s, 3H), 4.15 (q, 2H), 4.57 (q, 2H), 5.22 (s, 2H), 5.82 (s,
2H), 6.44 (s, 1H), 6.52 (s, 1H), 6.62 (dd, 1H), 6.85 (d, 1H),
7.00-7.30 (m, 3H);
[0182] To a solution of
ethyl-(E)-3-[2-Butyl-1-[2-(N-ethyltetrazol-5-yl)me-
thoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyp-
henyl)methyl]-2-propenoate (0.15 g, 0.25 ramol) in methanol (5 mL)
was added 3 mL of 1N sodium hydroxide. The reaction mixture was
allowed to stir at reflux for 4 h. The reaction mixture was washed
with diethyl ether and the aqueous layer was acidified with
concentrated HCl and extracted with ethyl acetate. The organic
extract was washed with brine and dried (Na.sub.2SO.sub.4). After
removing the solvent, reverse phase HPLC of the residue eluting
with 40% CH.sub.3CN/H.sub.2O containing 1% TFA afforded the title
compound as a brown solid (0.13 g, 91%): MS (ESI) m/e [M+H].sup.+
591; mp: 189-193.degree. C.; Anal.
(C.sub.28H.sub.30N.sub.6O.sub.7.9/4CF.sub.3COOH) calcd. C, 48.97;
H, 4.20; N, 9.93. found C, 49.20; H, 4.42; N, 10.21.
EXAMPLE 7
E-3-[2-Butyl-1-[2-(3-picolyl)oxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2--
methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic Acid Acetate
Salt
[0183] m.p. 181-183.degree. C. (dec).
EXAMPLE 8
E-3-[2-Butyl-1-[2-(3-carboxyphenyl)methoxy-4-methoxy]phenyl-1H-imidazol-5--
yl]-2-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0184] m.p. 127-129.degree. C. (dec).
EXAMPLE 9
E-3-[2-Butyl-1-[2-(N-methyl)carboamidomethoxy-4-methoxy]phenyl-1H-imidazol-
-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0185] m.p. 129-131.degree. C.
EXAMPLE 10
E-3-[2-Butyl-1-(2-hydroxyethyloxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(2-
-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid
[0186] m.p. 108-110.degree. C.
EXAMPLE 11
E-3-[2-Butyl-1-[2-[N-(4-isppropylphenyl)sulfonyl]carboxamido-methoxy-4-met-
hoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methy-
l]-2-propenoic acid
[0187] m.p. 144-146.degree. C.
EXAMPLE 12
E-3-[2-Butyl-1-[2-[N-(2-methylphenyl)sulfonyl]carboxamidomethoxy-4-methoxy-
]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-
-propenoic Acid
[0188] m.p. 146-148.degree. C.
EXAMPLE 13
E-3-[2-Butyl-1-[2-(N-dimethylaminosulfonyl)carboxamidomethoxy-4-methoxy]ph-
enyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-pr-
openoic Acid
[0189] m.p. 118-120.degree. C.
EXAMPLE 14
E-3-[2-Butyl-1-[2-(N-methanesulfonyl)carboxamidomethoxy-4-methoxy]phenl-1H-
-iridazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propnoic
Acid
[0190] m.p. 135-137.degree. C.
EXAMPLE 15
E-3-[2-Butyl-1-[2-(N-phenylcarbonyl)carboxamidomethoxy-4-methoxy]phenyl-1H-
-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0191] m.p. 89-91.degree. C.
EXAMPLE 16
E-3-[2-Butyl-1-[2-(2-tolulyl)oxy-4-methoxyl]phenyl-1H-imidazol-5-yl]-2-[(2-
-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic Acid
[0192] m.p. 228-229.degree. C.
EXAMPLE 17
E-3-[2-Butyl-1-[2-(N-t-butylsulfonyl)carboxamidomethoxy
-4-methoxy]phenyl-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxypheny-
l)methyl]-2-propenoic Acid
[0193] m.p. 142-144.degree. C.
EXAMPLE 18
E-3-[2-Butyl-1-[2-(2-(tetrazol-5-yl)benzyloxy-4-methoxy]phenyl-1H-imidazol-
-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid
[0194] m.p. 199-205.degree. C.
EXAMPLE 19
(E)-3-[2-Butyl-1-(2-(2,4-difluorobenzyloxy)-4-methoxy)phenyl-1H-imidazol-5-
-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid
[0195] m.p. 198-201.degree. C.
EXAMPLE 20
(E)-3-[2-Butyl-1-(2-(4-fluorobenzyloxy)-4-methoxy)phenyl-1H-imidazol-5-yl]-
-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0196] m.p. 204-206.degree. C.
EXAMPLE 21
(E)-3-[2-Butyl-1-[2-(5-chlorothiophen-5-yl)methoxy-4-methoxy]phenyl-1H-imi-
dazol
-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0197] m.p. 188-189.degree. C.
EXAMPLE 22
E-3-[2-Butyl-1-[2-(2-ethyl-2H-tetrazol-5-yl)benzyloxy-4-methoxyphenyl]-1H--
imidazol
-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0198] m.p. 175-181.degree. C.
EXAMPLE 23
(E)-3-[2-Butyl-1-[2-(1-ethyl-1H-tetrazol-5-yl)methoxy-4-methoxyphenyl]-1H--
imidazol
-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
acid
[0199] m.p. 185-190.degree. C.
EXAMPLE 24
(E)-3-[2-Butyl-1-[2-(2-propyl-2H-tetrazol-5-yl)methoxy-4-methoxyphenyl]-1H-
-imidazol
-5-yl]-2-[(2-mcthoxy-4,5-methylenedioxyphenyl)methyl]-2-projenoi- c
Acid
[0200] m.p. 110-118.degree. C.
EXAMPLE 25
(E)-3-[2-Butyl-[1-(2-carboxymethoxy).sub.4-methoxy)phenyl]-1H-imidazol-5-y-
l]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0201] a)
Ethyl-(E)-3-[2-butyl-1-(2-(methoxymethoxy).sub.4-methoxyphenyl)]-
-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propen-
oate
[0202] A solution of
1-(2-methoxymethoxy-4-methoxyphenyl)-1H-imidazol-5-ca- rboxaldehyde
(1.00 g, 2.976 mmol) of Example 3(b), ethyl hydrogen
2-(4,5-methylenedioxy-1-methoxybenzyl)-malonate (2.64 g, 8.930
mmol), piperidine(0.15 ml, 1.488 mmol) and acetic acid (0.085 ml,
1.488 mmol) in benzene (50 ml) was equipped with a Dean-Stark
apparatus, and stirred at reflux for 24 h. The solvent was removed
and the crude residue was extracted with ethyl acetate and washed
with 10% sodium carbonate solution, water, dried
(Na.sub.2SO.sub.4). After removing the solvent flash chromatography
of the residue (silica gel, 50% ethyl acetate/hexane) yielded the
title compound as a brown oil (1.03 g, 63%). Anal.
(C.sub.30H.sub.36N.sub.2O.sub.8) calcd: C, 65.18; H, 6.58; N, 5.07.
found: C, 64.85; H, 6.20; N, 4.93.
[0203] b)
Ethyl-(E)-3-[2-butyl-1-(2-hydroxy-4-methoxyphenyl)-1H-imidazol-5-
-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
[0204] To a solution of the
ethyl-(E)-3-[2-butyl-1-(2-(methoxymethoxy)4-me-
thoxyphenyl)]-1H-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmet-
hyl]-2-propenoate (1.00 g, 1.811 mmol) in ethanol (25 ml) was added
a catalytic amount of concentrated HCl. After stirring at reflux
for 5 h the solvent was removed and the residue was extracted with
ethyl acetate and washed with sodium bicarbonate (satd.), dried
(Na.sub.2SO.sub.4). After removing the solvent flash chromatography
of the residue (silica gel, 50%. ethyl acetate/hexane) gave the
title compound as a brown oil (0.856 g, 93%). Anal.
(C.sub.2gH.sub.32N.sub.2O.sub.7) calcd: C, 66.10; H, 6.36; N, 5.51.
found: C, 65.92; H, 6.01; N, 5.12.
[0205] c)
Ethyl-(E)-3-[2-butyl-1-(2-allylcarbomethoxy)-4-methoxyphenyl]-1H-
-imidazol-5S
yl-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoat-
e
[0206] To a solution of the
ethyl-(E)-3-[2-butyl-1-(2-hydroxy-4-methoxyphe- nyl)]-1H-imidazol
-5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2--
propenoate (0.38 g, 0.776 mmol) in DMF (10 ml) was added sodium
hydride (0.024 g, 0.996 mmol) and stirred at rt for 1 h under
argon. Allyl chloroacetate (0.110 ml, 0.919 mmol) was added to the
mixture and was allowed to stir for 18 h. The reaction was quenched
with water and extracted with ethyl acetate. The organic extracts
were washed with water, brine and dried (Na.sub.2SO.sub.4). After
removing the solvent flash chromatography of the residue (silica
gel, 50% ethyl acetate/hexane) afforded the title compound as a
brown oil (0.426 g, 92%): MS(ESI) nme 607.2 [M+H].sup.+.
[0207] d)
Ethyl-(E)-3-[2-butyl-1-(2-carbomethoxy)-4-methoxyphenyl]-1H-imid-
azol-5-yl-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
[0208] To a solution of
ethyl-(E)-3-[2-butyl-1-(2-allylcarbomethoxy)-4-met-
hoxy-phenyl]-1H-imidazol-5-yl-2-[(2-methoxy-4,5-methylenedioxy)phenylmethy-
l]-2-propenoate (0.47 g, 0.791 mmol) in dichloromethane (10 ml) was
added triethylsilane (0.70 ml, 4.384 mmol) and
tetrakis(triphenylphosphine)pall- adium(0) (0.20 g, 0.175 mmol),
respectively. After refluxing for 3 h, the reaction was quenched
with water. The mixture was extracted with ethyl acetate
(3.times.15 mL). The combined organic extracts were washed with
brine and dried (Na.sub.2SO.sub.4). After removing the solvent,
flash chromatography of the residue (silica gel, ethyl acetate)
gave the title compound as a brown solid (0.400 g, 91%): Anal.
(C.sub.30H.sub.34N.sub.2O- .sub.9) calcd: C, 63.58; H, 6.06; N,
4.94. found: C, 63.21; H, 5.87; N, 4.63.
[0209] e)
(E)-3-[2-Butyl-[1-[2-(carbomethoxy)-4-methoxyphenyl]-1H-imidazol-
-5-yl]-2-[(6-methoxy-3,4-methylenedioxyphenyl)methyl]-2-propenoic
acid
[0210] To a solution of
ethyl-(E)-3-[2-butyl-1-(2-carbomethoxy)-4-methoxyp-
henyl]-1H-imidazol-5-yl-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-p-
ropenoate (0.50 g, 0.902 mmol) in methanol (10 iml) was added a
solution of potassium hydroxide (0.065 g, 1.170 mmol) in water (4
ml). The reaction was allowed to stir at reflux for 6 h. The
organic solvent was removed and the aqueous layer was washed with
ether. The aqueous layer was acidified with concentrated HCl and
extracted with ethyl acetate. The combined organic extracts were
dried (Na.sub.2SO.sub.4) and evaporated to afford a white solid.
Crystallization from methanol yielded the title compound as a white
solid (0.456 g, 94%): .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
7.22 (d, J=10 Hz, 1H), 7.10 (s, 1H), 6.89 (s, 1H), 6.73 (d, 2H),
6.29 (s, 1H), 5.91 (s, 2H), 4.76 (dd, J=8 Hz, 20 Hz, 2H), 3.84 (s,
3H), 3.82 (s, 3H), 3.65 (s, 2H), 2.48 (m, 2H), 1.51 (p, 2H), 1.18
(sextet, 2H), 0.76 (t, 3H); MS(ESI) rne 539.2 [M+H].sup.+; mp:
164.degree. C., Anal. (C.sub.28H.sub.30N.sub.2O.sub.9) calcd: C,
62.43; H, 5.63; N, 5.20. found: C, 62.10; H, 5.32; N, 4.19.
EXAMPLE 26
E-3-[2-Butyl-1-[2-(3-carboxy)propoxy-4-methoxy]phenyl-1H-imidazol-5-yl]-2--
[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic Acid
[0211] m.p. 128-130.degree. C.
EXAMPLE 27
E-3-[1-(2-Carboxymethoxy-4-methoxy)phenyl-2-isopropyl-1H-imidazol-5-yl]-2--
[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic Acid
[0212] m.p. 256-258.degree. C.
EXAMPLE 28
E-3-[1-(2-Carboxymethoxy-4-methoxy)phenyl-2-isobutyl-1H-imidazol-5-yl]-2-[-
(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid
[0213] m.p. 264-266.degree. C.
EXAMPLE 29
E-3-[1-(2-Carboxymethoxy-4-methoxy)phenyl-2-(1-methyl)propyl-1H-imidazol-5-
-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic
Acid
[0214] m.p. 252-253.degree. C.
EXAMPLE 30
E-3-[2-Butyl-1-(2-carboxymethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(3--
methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid
[0215] m.p. 179-179.5.degree. C.
EXAMPLE 31
E-3-[2-Butyl-1-(2-carboxymethoxy-4-methoxy)pheny]-1H-imidazol-5-yl]-2-[(3,-
4-methylenedioxyphenyl)methyl]-2-propenoic acid
[0216] m.p. 157-158.degree. C.
EXAMPLE 32
E-3-[2-Butyl-1-(2-carboxymethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(2c-
hloro-4,5-methylenedioxyphenyl)methyl]-2-propenoic Acid
[0217] m.p. 228-230.degree. C.
EXAMPLE 33
E-3-[2-Butyl-1-(2-carboxymethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(2--
ethoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid
[0218] m.p. 131-133.degree. C.
EXAMPLE 34
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(4-me-
thoxyphenyl)methyl]-2-propenoic acid
[0219] m.p. 128-130.degree. C.
EXAMPLE 35
[0220]
E-3-[2-Buthyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]--
2-[(4,5-dimethoxyphenyl)methyl]-2-propenoic acid
[0221] M.P. 135-138.degree. C.
EXAMPLE 36
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(2,4--
dimethoxyphenyl)methyl]-2-propenoic acid
[0222] m.p. 145-147.degree. C.
EXAMPLE 37
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-1-2-[(3--
methoxyphenyl)methyl]-2-propenoic acid
[0223] m.p. 146-148.degree. C.
EXAMPLE 38
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(3-hy-
droxyphenyl)methyl]-2-propenoic acid
[0224] m.p. 129-131.degree. C.
EXAMPLE 39
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(4-hy-
droxyphenyl)methyl]-2-propenoic acid
[0225] m.p. 135-137.degree. C.
EXAMPLE 40
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[(2-hy-
droxy-4-methoxyphenyl)methyl]-2-propenoic acid
[0226] m.p. 140-143.degree. C.
EXAMPLE 41
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-inmidazol-5-yl]-2-(3,4--
difluorophenyl)methyl-2-propenoic Acid
[0227] m.p. 114-115.degree. C.
EXAMPLE 42
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-(3,4-d-
ichlorophenyl)mcthyl-2-propenoic Acid Dicyclohexyl Amine Salt
[0228] m.p. 113-114.degree. C.
EXAMPLE 43
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-(indol-
-6-yl)methyl-2-propenoic Acid
[0229] m.p. 161-162.degree. C.
EXAMPLE 44
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-(indol-
-5-yl)methyl-2-propenoic Acid
[0230] m.p. 165-167.degree. C.
EXAMPLE 45
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-[2,2-d-
imethyl-(1,3-benzodiox-5-yl)methyl]-2-propenoic acid
[0231] m.p. 124-127.degree. C.
EXAMPLE 46
E-3-[2-Butyl-1-(2-carbomethoxy-4-methoxy)phenyl-1H-imidazol-5-yl]-2-(pheny-
lmethyl)-2-propenoic acid
[0232] m.p. 128-130.degree. C.
EXAMPLE 47
[0233] Formulations for pharmaceutical use incorporating compounds
of the present invention can be prepared in various forms and with
numerous excipients. Examples of such formulations are given
below.
[0234] Inhalant Formulation
[0235] A compound of Formula I, (1 mg to 100 mg) is aerosolized
from a metered dose inhaler to deliver the desired amount of drug
per use.
1 Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of
Form. I) 2. Corn Starch 20 mg 3. Alginic acid 20 mg 4. Sodium
Alginate 20 mg 5. Mg stearate 1.3 mg 2.3 mg
[0236] Procedure for Tablets:
[0237] Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a
suitable mixer/blender.
[0238] Step 2 Add sufficient water portion-wise to the blend from
Step 1 with careful mixing after each addition. Such additions of
water and mixing until the mass is of a consistency to permit its
conversion to wet granules.
[0239] Step 3 The wet mass is converted to granules by passing it
through an oscillating granulator using a No. 8 mesh (2.38 mm)
screen.
[0240] Step 4 The wet granules are theh dried in an oven at
140.degree. F. (60.degree. C.) until dry.
[0241] Step 5 The dry granules are lubricated with ingredient No.
5.
[0242] Step 6 The lubricated granules are compressed on a suitable
tablet press.
[0243] Parenteral Formulation
[0244] A pharmaceutical composition for parenteral administration
is prepared by dissolving an appropriate amount of a compound of
formula I in polyethylene glycol with heating. This solution is
then diluted with water for injections Ph Eur. (to 100 ml). The
solution is then steriled by filtration through a 0.22 micron
membrane filter and sealed in sterile containers.
* * * * *