Phenyl derivatives useful as endothelin receptor antagonists

Novel phenyl derivatives which are useful as endothelin receptor antagonists.

The present invention relates to novel compounds, pharmaceutical 
compositions containing these compounds and their use as endothelin 
receptor antagonists. 
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. 
In vivo, endothelin has pronounced effects on blood pressure and cardiac 
output. An intravenous bolus injection of ET (0.1 to 3 nmol/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. 
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. 
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. 
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. 
ET has also been implicated in myocardial ischemia (Nicholas 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 Lerman 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). 
Further, endothelin has been found to be a potent constrictor of isolated 
mammalian airway tissue including a human bronchus (Uchida et al., Eur. J. 
of Pharm. 154: 227-228, 1998, 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. 
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, February 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) endotoxin shock and other endotoxin induced diseases 
(Biochem. Biophys. Res. Commun., 161: 1220-1227, 1989, Acta Physiol. 
Scand. 137: 317-318, 1989) inflammatory skin diseases, (Clin Res. 41:451 
and 484, 1993) and macular degeneration. 
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. Obstet. 
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). 
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). 
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). 
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, congestive heart failure, pulmonary hypertension, 
asthma, atherosclerosis, macular degeneration, 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 or treatment of restenosis, diabetes, preclampsia of pregnancy, 
bone remodeling, kidney transplant, male contraceptives, infertility and 
priaprism and benign prostatic hypertrophy. 
In a first aspect the present invention provides compounds of formula (I): 
##STR1## 
wherein: R is a group Ar as defined hereinafter; 
R.sup.1 is hydrogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 
X(CH.sub.2).sub.p Ar; or a methylenedioxy group attached to two adjacent 
ring carbon atoms; 
R.sup.2 is --(CH.sub.2).sub.x C(O)N(R.sup.4)S(O).sub.y R.sup.5, 
--(CH.sub.2).sub.x S(O).sub.y N(R.sup.4)C(O)R.sup.5, --(CH.sub.2).sub.x 
C(O)N(R.sup.4)C(O)R.sup.5 --(CH.sub.2).sub.x S(O).sub.y 
N(R.sup.4)S(O).sub.y R.sup.5, --(CH.sub.2).sub.x CO.sub.2 R.sup.4, or 
tetrazol-5-yl optionally substituted by C.sub.1-6 alkyl; 
R.sup.3 is X(CH.sub.2)pAr or --X(CH.sub.2)pR.sup.4 or a group of the 
formula (a): 
##STR2## 
Ar is a group of formula (b) or (c): 
##STR3## 
or Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl, 
oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 
imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, 
thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or 
pyrimidyl; all of which may be unsubstituted or substituted by one or more 
R.sup.7 or R.sup.8 groups; 
A is C.dbd.O, or (C(R.sup.4).sub.2).sub.m ; 
each B is independently --CH.sub.2 -- or --O--; 
R.sup.4 is hydrogen or C.sub.1-6 alkyl; 
R.sup.5 is hydrogen or C.sub.1-10 alkyl or Ar, both of which may be 
unsubstituted or substituted by one or two Cl, F, Br, hydroxy, 
--XC.sub.1-5 alkyl, C.sub.1-5 alkyl, NO.sub.2, tetrazol-5-yl optionally 
substituted by C.sub.1-6 alkyl, or R.sup.5 is --N(R.sup.4).sub.2 ; 
R.sup.6 is hydrogen, R.sup.10, CO.sub.2 R.sup.11, CO.sub.2 
C(R.sup.10).sub.2 O(CO)XR.sup.11, PO.sub.3 (R.sup.11).sub.2, SO.sub.2 
NR.sup.11 R.sup.10, NR.sup.11 SO.sub.2 R.sup.10, CONR.sup.11 SO.sub.2 
R.sup.10, SO.sub.3 R.sup.11, S(O).sub.q R.sup.11, S(O).sub.q 
N(R.sup.11)C(O)R.sup.10, S(O).sub.q N(R.sup.11)S(O).sub.q R.sup.10, 
C(O)N(R.sup.11)C(O)R.sup.10, N(R.sup.11)C(O)R.sup.10, N(R.sup.11).sub.2, 
N(R.sup.11)C(O)NR.sup.11, P(O)(OR.sup.11)R.sup.11, CN, --CO.sub.2 
(CH.sub.2).sub.m C(O)N(R.sup.4).sub.2, C(R.sup.10).sub.2 
N(R.sup.11).sub.2, C(O)N(R.sup.4).sub.2, OR.sup.4, or tetrazolyl 
optionally substituted by C.sub.1-6 alkyl; 
R.sup.7 and R.sup.9 are independently hydrogen, R.sup.10, OH, C.sub.1-8 
alkoxy, S(O).sub.q R.sup.10, N(R.sup.4).sub.2, Br, F, I, Cl, CF.sub.3, 
NO.sub.2, NHCOR.sup.4, R.sup.12 CO.sub.2 R.sup.11, --X--R.sup.13 --Y, 
--X(CR.sup.4)pOR.sup.4, S(CH.sub.2)pCO.sub.2 H, (CH.sub.2)pX--R.sup.13 
--X(CH.sub.2)pCONR.sup.11 SO.sub.2 R.sup.10, (CH.sub.2)pXCONR.sup.11 
SO.sub.2 R.sup.10, or --X(CH.sub.2).sub.p R.sup.6 wherein each methylene 
group within --X(CH.sub.2).sub.p R.sup.6 may be unsubstituted or 
substituted by one or two --(CH.sub.2).sub.p Ar groups; 
R.sup.8 is hydrogen, R.sup.10, OH, C.sub.1-5 alkoxy, S(O).sub.q R.sup.10, 
N(R.sup.4).sub.2, Br, F, I, Cl or NHCOR.sup.4 wherein the C.sub.1-5 alkoxy 
may be unsubstituted or substituted by OH, methoxy or halogen; 
R.sup.10 is hydrogen, Ar, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 
alkynyl, all of which may be unsubstituted or substituted by one or more 
OH, CH.sub.2 OH, N(R.sup.4).sub.2 or halogen; or R.sup.10 is 
N(R.sup.4).sub.2 ; 
R.sup.11 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl or 
C.sub.2-8 alkynyl, all of which may be unsubstituted or substituted by one 
or more OH, N(R.sup.4).sub.2, CO.sub.2 R.sup.14, halogen or XC.sub.1-5 
alkyl; or R.sup.11 is (CH).sub.p Ar; 
R.sup.12 is divalent Ar, C.sub.1-10 alkylene, C.sub.1-10 alkylidene, 
C.sub.2-10 alkenylene, C.sub.2-10 alkynylene, all of which may be 
unsubstituted or substituted by one or more OH, CH.sub.2 OH, 
N(R.sup.4).sub.2 or halogen; 
R.sup.13 is a bond, C.sub.1-10 alkylene, C.sub.1-10 alkenylene, C.sub.1-10 
alkylidene, C.sub.1-10 alkynylene, all of which may be linear or branched, 
or phenylene, all of which may be unsubstituted or substituted by one or 
more OH, N(R.sup.4).sub.2, COOH or halogen; 
R.sup.14 is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-7 
alkynyl; 
X is (CH.sub.2).sub.p, O, NR.sup.4 or S(O).sub.q ; 
Y is CH.sub.3 or X(CH.sub.2).sub.p Ar; 
q is zero, one or two; 
p is an integer from 0 to six; 
m is 1, 2 or 3; 
n is 1 to 4; 
x is 0 to 4; 
y is 1 or 2; 
the dotted line signifies the optional presence of a bond such that .sup.- 
- - represents a single or double bond; 
and pharmaceutically acceptable salts thereof. 
In the compounds of formula (I) all defined alkyl, alkenyl and alkoxy 
groups and moieties may be straight or branched. Thus for example a 
C.sub.1-6 alkyl group may be methyl, ethyl, n-propyl, n-butyl, n-pentyl, 
n-hexyl or any branched isomers thereof such as isopropyl, t-butyl, 
sec-pentyl, and the like. The term "halogen" is used to mean iodo, fluoro, 
chloro or bromo. 
In the compounds of formula (I) the group R preferably represents a group 
(b). 
##STR4## 
The substituents R.sup.7, R.sup.8 and R.sup.9 may occupy any available 
position on the ring. Preferably however, R.sup.7 is located at position 
2, R.sup.8 at position 3 and R.sup.9 at position 4 relative to the phenyl 
ring to which group (b) is attached. 
R.sup.1 preferably represents hydrogen; C.sub.1-6 alkoxy, e.g. methoxy, 
propoxy; X(CH.sub.2).sub.p Ar; or methylenedioxy. When R.sup.1 is 
X(CH.sub.2).sub.p Ar, X preferably represents O, p preferably represents 1 
and Ar preferably represents a group (b); in this case R.sup.7, R.sup.8 
and R.sup.9 each preferably represent H, such that R.sup.1 represents 
benzyloxy. 
R.sup.2 is preferably --(CH.sub.2).sub.x CO.sub.2 R.sup.4 ; x is suitably 0 
and R.sup.4 is suitably hydrogen. Most preferably R.sup.2 represents 
--CO.sub.2 H. 
R.sup.3 is preferably a group X(CH.sub.2)pAr, cyclohexyl or C.sub.1-4 
alkyl. Most preferably R.sup.3 is a group --X(CH.sub.2).sub.p Ar wherein 
Ar is a group (c). In said group (c) A is preferably CH.sub.2, B is 
preferably O, R.sup.7 is preferably hydrogen and R.sup.8 is preferably 
hydrogen or C.sub.1-6 alkoxy e.g. methoxy. Advantageously R.sup.3 is 
dihydrobenzofuranyl. 
When R.sup.5 represents a group Ar, this is preferably optionally 
substituted phenyl. 
R.sup.6 preferably represents phenyl, pyridyl, hydrobenzofuranyl, 
benzodioxanyl, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, all 
of which may be unsubstituted or substituted by one or two CO.sub.2 
R.sup.11, OH, CH.sub.2 OH, N(R.sup.4).sub.2 Br, Cl, F or I; hydrogen, 
CO.sub.2 R.sup.11, CO.sub.2 C(R.sup.10).sub.2 O(CO)XR.sup.11, PO.sub.3 
(R.sup.11).sub.2, SO.sub.2 NR.sup.11 R.sup.10, NR.sup.11 SO.sub.2 
R.sup.10, CONR.sup.11 SO.sub.2 R.sup.10, SO.sub.3 R.sup.11, S(O).sub.q 
C.sub.1-4 alkyl, S(O).sub.q N(R.sup.11)C(O)R.sup.10, S(O).sub.q 
N(R.sup.11)S(O).sub.q R.sup.10, C(O)N(R.sup.11)C(O)R.sup.10, 
N(R.sup.11)C(O)R.sup.10, N(R.sup.11).sub.2, N(R.sup.11)C(O)NR.sup.11, 
P(O)(OR.sup.11)R.sup.11, CN, --CO.sub.2 (CH.sub.2).sub.m 
C(O)N(R.sup.4).sub.2, C(R.sup.10).sub.2 N(R.sup.11).sub.2, 
C(O)N(R.sup.4).sub.2, OR.sup.4, or tetrazolyl optionally substituted by 
C.sub.1-6 alkyl. 
R.sup.7 and R.sup.9 preferably independently represent hydrogen, OH, 
C.sub.1-8 alkoxy, N(R.sup.4).sub.2, Br, F, I, Cl, NO.sub.2, R.sup.12 
CO.sub.2 R.sup.11, --OCH(CH.sub.3)CO.sub.2 H, --X(CR.sup.4)pOR.sup.4, 
C.sub.1-4 alkyl, NH(CO)CH.sub.3, pyridyl, -phenyl, 
(CH.sub.2)p-O-Phenyl(CO.sub.2 H)-OCH.sub.2 
C(O)NHS(O.sub.2)-phenyl-R.sup.4, (CH.sub.2)p-O-Phenyl(CO.sub.2 
H)-OCH.sub.2 C(O)NHS(O.sub.2)-C.sub.1-4 alkyl, 
(CH.sub.2)p-O-C(O)NHS(O.sub.2)-phenyl-R.sup.4, 
(CH.sub.2)p-O-C(O)NHS(O.sub.2)-C.sub.1-4 alkyl, S(O)qC.sub.1-5 alkyl, 
S(CH.sub.2)pCO.sub.2 H or --X(CH.sub.2).sub.p R.sup.6. 
In the context of the group R, R.sup.7 and R.sup.9 preferably do not 
represent hydrogen. In particular in the group R, R.sup.7 preferably 
represents C.sub.1-8 alkoxy e.g. methoxy or a group --X(CH.sub.2)pR.sup.6, 
wherein X preferably represents O, p is preferably 1 or 2, and R.sup.6 is 
preferably selected from --CO.sub.2 R.sup.11 wherein R.sup.11 is 
preferably H; N(R.sup.11).sub.2 wherein R.sup.11 is preferably H or 
C.sub.1-4 alkyl, e.g. methyl; C(O)N(R.sup.4).sub.2 wherein R.sup.4 is 
preferably H or C.sub.1-4 alkyl, e.g. methyl; --CONR.sup.11 SO.sub.2 
R.sup.10 wherein R.sup.11 is preferably H and R.sup.10 is preferably 
phenyl; tetrazolyl optionally substituted by C.sub.1-6 alkyl e.g. ethyl; 
or one or more of halogen e.g. Cl or F, CH.sub.2 OH, or --CO.sub.2 
R.sup.11 wherein R.sup.11 is preferably H. R.sup.9 preferably represents 
C.sub.1-8 alkoxy e.g. methoxy, N(R.sup.4).sub.2 e.g. amino or 
dimethylamino, or NO.sub.2. Especially preferred values for R.sup.6 are 
phenyl substituted by CO.sub.2 H or by CH.sub.2 OH. 
R.sup.8 preferably represents hydrogen, OH, C.sub.1-5 alkoxy, 
N(R.sup.4).sub.2, Br, F, I, Cl C.sub.1-4 alkyl, NH(CO)CH.sub.3, or S(O)q 
C.sub.1-5 alkyl wherein the C.sub.1-5 alkoxy may be unsubstituted or 
substituted by OH, methoxy or halogen. In the context of the group R, 
R.sup.8 advantageously represents hydrogen. 
R.sup.10 is preferably hydrogen, phenyl, benzodioxanyl or pyridyl all of 
which may be substituted or unsubstituted by one or two C.sub.1-4 alkyl 
groups; C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkenyl, 
C.sub.2-10 alkynyl, all of which may be unsubstituted or substituted by 
one or two OH, CH.sub.2 OH, N(R.sup.4).sub.2 or Br, Cl, F or I, or 
R.sup.10 is N(R.sup.4).sub.2. In the groups CO.sub.2 C(R.sup.10).sub.2 
O(CO)XR.sup.11, SO.sub.2 NR.sup.11 R.sup.10, NR.sup.11 SO.sub.2 R.sup.10, 
CONR.sup.11 SO.sub.2 R.sup.10, S(O).sub.q N(R.sup.11)C(O)R.sup.10, 
S(O).sub.q N(R.sup.11)S(O).sub.q R.sup.10, C(O)N(R.sup.11)C(O)R.sup.10, 
N(R.sup.11)C(O)R.sup.10 and C(R.sup.10).sub.2 N(R.sup.11).sub.2, R.sup.10 
preferably represents, hydrogen, C.sub.1-10 alkyl, eg C.sub.1-6 alkyl, 
advantageously C.sub.1-4 alkyl or optionally substituted phenyl. 
R.sup.11 is preferably hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl or 
C.sub.2-8 alkynyl, all of which may be unsubstituted or substituted by one 
or two OH, N(R.sup.4).sub.2, CO.sub.2 R.sup.14, Br, Cl, F or I or 
XC.sub.1-5 alkyl; or R.sup.11 is (CH.sub.2).sub.p Ar. When R.sup.11 is 
(CH.sub.2).sub.p Ar, p is preferably zero or 1 and Ar is preferably 
optionally substituted phenyl. Most preferably R.sup.11 is hydrogen, 
C.sub.1-10 alkyl, eg C.sub.1-6 alkyl, advantageously C.sub.1-4 alkyl, or 
optionally substituted phenyl. 
R.sup.12 is preferably phenylene, pyridylene, C.sub.1-10 alkylene, 
C.sub.1-10 alkylidene, C.sub.2-10 alkenylene, C.sub.2-10 alkynylene, all 
of which may be unsubstituted or substituted by one or two OH, CH.sub.2 
OH, N(R.sup.4).sub.2 or Br, Cl, F or I. 
Preferred compounds of formula (I) include: 
(E)-3-[2-(2,4-Dimethoxyphenyl)phen-1-yl]-2-(3,4-methylenedioxybenzyl)prop-2 
-enoic acid; 
(E)-3-[2-(2-Carboxymethoxy-4-methoxyphenyl)-3-propyloxyphen-1-yl]-2-(3,4-me 
thylenedioxybenzyl)prop-2-enoic acid; 
(E)-3-[3-n-Propoxy-2-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylphen-1-yl] 
-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-(2-carboxymethoxy-4-methoxy)phenylphen-1-yl]-2-[(2-met 
hoxy-4,5-methylenedioxyphenyl]methyl-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-N-phenylsulfonyl)carboxamidomethoxy-4-methoxy]ph 
enylphen-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic 
acid 
(E)-3-[2-[2-(Carboxyphenyl)methoxy-4-methoxy]phenylphen-1-yl]-2-[2-methoxy- 
4,5-methylenedioxyphenyl]methyl-2-propenoic acid 
(E)-3-[5-Benzyloxy-2-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylphen-1-yl] 
-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]propenoic acid 
(E)-3-[3,4-Methylenedioxy-2-[2-(2-Carboxyphenyl)methoxy-4-methoxy]phenylphe 
n-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]propenoic acid 
(E)-3-[3-methoxy-2-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylphen-1-yl]-2 
-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(5-tetrazolyl)methoxy-4-methoxy]phenylphen-1-yl]-2- 
[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-carboxy-4-chlorophenyl)methoxy-4-methoxy]phenylp 
hen-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-ethyl-1H-tetrazol-5-yl)methoxy-4-methoxy]phenylp 
hen-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylphen-1-yl] 
-2-[(3,4-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[4-n-Propoxy-2-[2-(2-carboxyphenyl)methoxy-4-methoxy]phenylphen-1-yl] 
-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-hydroxymethylphenyl)methoxy-4-methoxy]phenylphen 
-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[5-n-Propoxy-2-[2-(2-carboxylphenyl)methoxy-4-methoxy]phenylphen-1-yl 
]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-carboxy-4-fluorophenyl)methoxy-4-methoxy]phenylp 
hen-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-carboxyphenyl)methoxy-4-amino]phenylphen-1-yl]-2 
-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(carboxyphenyl)methoxy-4-nitro]phenylphen-1-yl]-2-[ 
(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(N,N-dimethylaminoethoxy)-4-methoxy]phenylphen-1-yl 
]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[3-n-Propoxy-2-[2-(2-carboxyphenyl)methoxy-4-dimethylamino]phenylphen 
-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[2-[2-(N,N-dibutylaminocarboxymethoxy)-4-methoxy]phenylphen-1-yl]-2-[ 
(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[2-[2-(N-phenylsulfonyl)methylenecarbamoyl-4-methoxy]phenylphen-1-yl] 
-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[2-[2-(2-hydroxymethylphenyl)methoxy-4-dimethylamino]phenylphen-1-yl] 
-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[2-[2-(2-hydroxymethylphenyl)methoxy-4-methoxy]phenylphen-1-yl]-2-[(2 
-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid 
(E)-3-[2-[2-(2-carboxyphenyl)methoxy-4-dimethylamino]phenylphen-1-yl]-2-[(2 
-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid and 
pharmaceutically acceptable salts thereof. 
Preferred compounds according to the invention include: 
(E)-3-[3-n-Propoxy-2-[(2-carboxyphenyl)methoxy-4-methoxy]phenylphen-1-yl]-2 
-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid; and 
(E)-3-[3-n-Propoxy-2-[2-(2-hydroxymethylphenyl)methoxy-4-methoxy]phenylphen 
-1-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid. 
It will be appreciated that for use in medicine the salts of formula (I) 
should be physiologically acceptable. Suitable physiologically acceptable 
salts will be apparent to those skilled in the art. Compounds of formula 
(I) which contain an acidic group eg a carboxyl function, may form salts 
with bases and suitable salts include for example inorganic base salts 
such as sodium, potassium or calcium salts, and organic base salts such as 
phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine and 
diethanolamine salts. Compounds of formula (I) containing a basic function 
eg an amine group may form salts with inorganic acids eg. hydrochloric, 
hydrobromic, sulphuric, nitric or phosphoric acid; or organic acids eg. 
succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, 
p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid. Other 
non-physiologically acceptable salts eg. oxalates may be used, for example 
in the isolation of compounds of formula (I) and are included within the 
scope of this invention. Also included within the scope of the invention 
are solvates and hydrates of compounds of formula (I). 
Also included in the invention are pharmaceutically acceptable salt 
complexes of the compounds of this invention which can form salts. 
It will be appreciated that the compounds of formula (I) may contain one or 
more asymmetric centres and may therefore exist in the form of optical 
isomers (enantiomers). The present invention includes within its scope all 
such enantiomers and mixtures, including racemic mixtures, thereof. In 
addition, all possible diastereomeric forms (individual diastereomers and 
mixtures thereof) of compounds of formula (I) are included within the 
scope of the invention. All geometrical isomers are also contemplated to 
be within the scope of the present invention. 
In a further aspect the present invention provides a process for the 
preparation of a compound of formula (I) comprising: 
(a) to prepare a compound (I) wherein the dotted line represents a bond, 
reaction of a compound of formula (II): 
##STR5## 
or a protected form or precursor thereof (as defined hereinafter) with a 
compound of formula (III): 
##STR6## 
(wherein R.sup.2 and R.sup.3 are as defined for formula (I) hereinabove); 
followed if necessary or desired by: 
(b) conversion of one compound of formula (I) into a different compound of 
formula (I) e.g. 
(i) when formula (I) contains an ester group e.g. (CH.sub.2).sub.x CO.sub.2 
R.sup.4 or CO.sub.2 R.sup.11 wherein R.sup.4 or R.sup.11 is alkyl, 
conversion to a corresponding compound wherein R.sup.4 or R.sup.11 
represents hydrogen; 
(ii) wherein - - - represents a double bond, hydrogenation to a single 
bond; 
(iii) when formula (I) contains a hydroxy group (e.g. in R.sup.7, R.sup.8 
or R.sup.9) conversion to a different group, eg a group O(CH.sub.2)Ar 
where Ar is optionally substituted phenyl, by methods well known in the 
art; and/or 
salt formation. 
Process (a) may be effected using standard procedures for the condensation 
of an aldehyde with an activated CH group. Thus for example the reaction 
may be effected in a solvent such as benzene, using reflux conditions and 
a Dean-Stark trap, or heating in the presence of pyridine and acetic acid. 
Conversion of an ester of formula (I) into an acid may be carried out using 
conventional deprotection techniques e.g. hydrolysis. 
An aldehyde of formula (II) may be prepared from a compound of formula 
(IV): 
##STR7## 
wherein Ar.sup.1 and R.sup.1a are as defined above for formula (II) and 
R.sup.15 is a group convertible to --CHO, such as an alcohol --CH.sub.2 OH 
or 4,4-dimethyl-2-oxazoline; or a protected form or precursor thereof. 
Conversion of R.sup.15 may be effected by standard methods; for example an 
oxazoline group may be alkylated with iodomethane followed by reduction 
with sodium borohydride and hydrolysis and oxidation of an alcohol may be 
effected using activated manganese dioxide. 
A compound of formula (IV) may be prepared by coupling appropriately 
substituted phenyl derivatives according to processes well known in the 
art. Thus for example when R represents a group (a) 
a compound of formula (V); 
##STR8## 
wherein R.sup.7, R.sup.8 and R.sup.9 are as hereinbefore defined, or a 
protected form or precursor thereof, may be coupled, via a Grignard 
derivative, with a compound of formula (VI): 
##STR9## 
wherein R.sup.15 represents oxazoline and R.sup.1 is as hereinbefore 
defined or a protected form or precursor thereof. 
Alternatively a compound of formula (VII): 
##STR10## 
or a protected form or precursor thereof may be coupled with a compound of 
formula (VIII): 
##STR11## 
wherein R.sup.1 and R.sup.15 are as defined for formula (IV) above, or a 
protected form or precursor thereof in the presence of 
Pd(PPh.sub.3).sub.4. 
A compound of formula (VII) may be prepared by reaction of a corresponding 
organometallic derivative (eg lithium or Grignard) with a trialkyl borate 
followed by hydrolysis. 
A compound of formula (VIII) may be prepared by reacting a compound of 
formula (IX): 
##STR12## 
or a protected form or precursor thereof with iodine. 
It will be appreciated by those skilled in the art that the substituents 
R.sup.1, R.sup.7, R.sup.8 and R.sup.9 may be introduced at any appropriate 
stage of the synthesis, preferably at an early stage, using methods well 
known in the art. In some of the reactions depicted above, particularly 
those in the early stages of the overall synthesis, one or more of the 
substituents R.sup.1, R.sup.7, R.sup.8 and R.sup.9 may therefore represent 
a precursor for the eventual substituent. A precursor for any of the 
substituents R.sup.1, R.sup.7, R.sup.8 and R.sup.9 means a group which may 
be derivatised or converted into the desired group R.sup.1, R.sup.7, 
R.sup.8 and R.sup.9. It will be further appreciated that it may be 
necessary or desirable to protect certain of these substituents (or their 
precursors) at various stages in the reaction sequence. Suitable 
precursors and protecting groups are well known to those skilled in the 
art, as are methods for their conversion or removal respectively. 
Thus for example, when Ar represents a group (b) 
##STR13## 
wherein R.sup.7 represents a substituted benzyloxy group, this may be 
introduced subsequent to the coupling reaction between compounds (II) and 
(III), the earlier preparative stages being effected with intermediates 
wherein R.sup.7 represents hydroxy, which may be protected as necessary, 
for example as a methoxymethyl ether. Similarly when R.sup.7 or R.sup.9 
represents a group O(CH.sub.2).sub.p CO.sub.2 R.sup.11 it may be formed 
from a precursor hydroxy group by reaction with an appropriate halo ester 
e.g. ethyl bromoacetate. 
Compounds of the present invention are endothelin receptor antagonists and 
as such are expected to be 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, stroke, cerebrovascular vasospasm, myocardial ischemia, 
angina, heart failure, pulmonary hypertension, atherosclerosis, as an 
adjunct in angioplasty for prevention of restenosis and benign prostatic 
hypertrophy. Preferably the compounds will be useful in the treatment of 
hypertension, renal failure and/or cerebrovascular disease. 
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). 
The present invention also provides the use of a compound of formula (I) in 
the manufacture of a medicament for antagonizing endothelin receptors, eg 
for treatment of any of the condition listed hereinabove. 
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. The present invention therefore provides 
in a further aspect pharmaceutical compositions comprising a novel 
compound of formula (I) as hereinbefore defined or a pharmaceutically 
acceptable salt thereof and a pharmaceutically acceptable carrier or 
excipient. 
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. 
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. 
Typical parenteral compositions consist of a solution or suspension of the 
sterile 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. 
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. 
A typical suppository formulation comprises a compound of Formula (I) 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. 
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. 
Preferably the composition is in unit dosage form, for example a tablet, 
capsule or metered aerosol dose, so that the patient may administer to 
himself a single dose. 
Each dosage unit for oral administration contains suitably from 0.1 mg to 
500 mg and preferably from 1 mg to 100 mg 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 to 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). 
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. 
No unacceptable toxicological effects are expected when compounds of the 
invention are administered in accordance with the present invention. 
The biological activity of the compound of Formula (I) are demonstrated by 
the following tests: 
I. Binding Assay 
A) Membrane Preparation 
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. 
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 -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. 
B) [.sup.125 I]ET-1 Binding Protocol 
[.sup.125 I]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 HCl, 
10 mM 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.125 I]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%. 
IC.sub.50 's for the compounds of this invention range from 0.35 nm to 40 
.mu.m. 
II In Vitro Vascular Smooth Muscle Activity 
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.2 PO.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% 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. 
ET-1 induced vascular contractions are expressed as a percentage of the 
response elicited by 60 mM KCl for each individual tissue which is 
determined at the beginning of each experiment. Data are expressed as the 
mean .+-. S.E.M. Dissociation constants (K.beta.) of competitive 
antagonists were determined by the standard method of Arunlakshana and 
Schild. The potency range for compounds of this invention range from 2.4 
nM to 10 .mu.M. 
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. 
Inhalant Formulation 
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. 
______________________________________ 
Tablets 
Ingredients Per Tablet 
______________________________________ 
1. Active ingredient 
40 mg 
(Cpd of Form. I) 
2. Corn Starch 20 mg 
3. Aliginic acid 20 mg 
4. Sodium alginate 20 mg 
5. Mg stearate 1.3 mg 
______________________________________ 
Procedure for tablets: 
Step 1. Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable 
mixer/blender. 
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. 
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. 
Step 4. The wet granules are then dried in an oven at 140.degree. F. 
(60.degree. C.) until dry. 
Step 5. The dry granules are lubricated with ingredient No. 5. 
Step 6. The lubricated granules are compressed on a suitable tablet press. 
Parenteral Formulation 
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 (to 100 ml). The solution is then steriled by filtration 
through a 0.22 micron membrane filter and sealed in sterile containers. 
The following examples are illustrative and are not limiting of the 
compounds of this invention. 
Description 1 
4,4-Dimethyl-2-(2-[2,4-dimethoxyphenyl]phenyl)-2-oxazoline. 
A suspension of magnesium powder (409 mg, 16.8 mmol) in THF (10 ml) 
containing a few crystals of iodine was heated whilst a solution of 
1-bromo-2,4-dimethoxybenzene (3.65 g, 16.8 mmol) in THF (20 ml) was added 
dropwise over 20 minutes. After completion of the addition, the mixture 
was refluxed for 1.25 hours and then allowed to cool to room temperature. 
The Grignard solution was transferred via syringe to a solution of 
2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (J. Org. Chem., 1978, 43, 
1372, 2.50 g, 12.9 mmol) in THF (10 ml) at room temperature and the 
mixture was stirred at room temperature for 42 hours. Saturated ammonium 
chloride solution was added and the product was extracted into diethyl 
ether. The extracts were dried (K.sub.2 CO.sub.3) and concentrated. 
Purification by column chromatography on silica gel (elution with 40-60% 
ethyl acetate in iso-hexane) gave the title compound as a viscous oil. 
Yield 4.029 g (84%). 
.sup.1 H NMR (CDCl.sub.3): 1.26 (6H, s), 3.71 (3H, s), 3.78 (2H, s), 3.85 
(3H, s), 6.47 (1H, d, J=2.5 Hz), 6.54 (1H, dd, J=2.2 and 8.2 Hz), 7.16 
(1H, d, J=8.2 Hz), 7.26-7.49 (3H, m), 7.83 (1H, m)ppm. 
.sup.13 C NMR (CDCl.sub.3): 28.1, 55.3, 66.9, 79.4, 98.1, 103.8, 123.6, 
126.7, 128.9, 129.7, 130.2, 130.5, 131.2, 137.9, 157.3, 160.3, 164.0ppm. 
IR (thin film): 1645, 1612 cm.sup.-1. 
MS (CI): 312 (MH.sup.+), HRMS 312.1599, calculated for C.sub.19 H.sub.21 
NO.sub.3 +H, 312.1599. 
Description 2 
2-(2,4-Dimethoxyphenyl)benzaldehyde 
A solution of 4,4-dimethyl-2-(2-[2,4-dimethoxyphenyl]phenyl)-2-oxazoline 
(3.88 g, 12.5 mmol) and methyl iodide (6.2 ml) in nitromethane (25 ml) was 
warmed at 70.degree. C. under argon overnight. The solvent was removed on 
the rotary evaporator to form a gum which was redissolved in 
dichloromethane/diethyl ether and then reconcentrated to give a foam. 
The foam was stirred in ethanol (35 ml) at room temperature under argon and 
sodium borohydride (290 mg) was added portionwise over 10 minutes. After 
stirring for 1 hour, more sodium borohydride (60 mg) was added and 
stirring was continued at room temperature for a further 1 hour. The 
ethanol was removed on the rotary evaporator and the residue was stirred 
in 2 N HCl (60 ml). After 2 hours, the mixture was partitioned between 
water and diethyl ether/ethyl acetate/dichloromethane. The aqueous layer 
was extracted with further portions of ethyl acetate and the combined 
extracts were washed with saturated sodium bicarbonate solution and brine 
and then dried (mgSO.sub.4) and concentrated to give a brown gum. This was 
triturated with diethyl ether and the ether solution was concentrated to 
give an orange oil. The remaining gum was stirred in THF (30 ml, 2 N HCl 
(30 ml) for 1 hour. The THF was removed on the rotary evaporator and the 
aqueous residue was worked up as above to give a brown oil which was 
combined with the orange oil isolated above. Column chromatography on 
silica gel (elution with 3:1 hexane:ethyl acetate) gave the title compound 
as an orange gum which slowly solidified on standing. Yield 1.423 g (47%). 
.sup.1 H NMR (CDCl.sub.3): 3.72 (3H, s), 3.87 (3H, s), 6.54 (1H, d, J=2.5 
Hz), 6.61 (1H, dd, J=.24 and 8.5 Hz), 7.20 (1H, d, J=8.5 Hz), 7.33 (1H, 
m), 7.44 (1H, m), 7.62 (1H, m), 7.97 (1H, dd, J=1.7 and 7.7 Hz), 9.79 (1H, 
d, J=0.8 Hz)ppm. 
.sup.13 C NMR (CDCl.sub.3): 55.4, 55.5, 98.5, 104.9, 119.5, 126.6, 127.4, 
131.4, 132.0, 133.6, 134.2, 141.7, 157.6, 161.4, 192.8ppm. 
IR (thin film): 1690 cm.sup.-1. 
MS (CI, ammoinia): 243 (MH.sup.+), 260 MNH.sub.4.sup.+), HRMS 242.0943 
(M.sup.+), C.sub.15 H.sub.14 O.sub.3 requires 242.0943. 
Description 3 
3-Propyloxybenzyl alcohol 
Method A 
A solution of 3-hydroxybenzyl alcohol (5.805 g, 46.8 mmol) in dry dimethyl 
formamide (30 ml) was added over 15 minutes to a suspension of sodium 
hydride (1.908 g of 60% dispersion in mineral oil, 47.7 mmol, previously 
washed with n-hexane) in dry dimethyl formamide (60 ml). After completion 
of the addition , the mixture was stirred at room temperature for 15 
minutes and then 1-iodopropane (11.9 g, 6.9 ml, 70.2 mmol) was added via 
syringe. The mixture was stirred at room temperature for 5 hours and then 
cautiously quenched with 2 N HCl. The solution was partitioned between 2 N 
HCl and ethyl acetate and the product was extracted into ethyl acetate. 
The extracts were washed successively with 5% sodium hydroxide solution, 
water, 10% sodium thiosulfate solution and brine. Drying (MgSO.sub.4) and 
evaporation gave crude product. Purification by flash chromatography on 
silica gel (elution with 1:1 diethyl ether--n-hexane) gave the title 
compound as a colourless oil. Yield 6.319 g (81%). 
Method B 
A mixture of 3-hydroxybenzoic acid (10 g, 0.072 mol), potassium carbonate 
(22.0 g, 0.159 mol) and 1-iodopropane (20.5 ml, 35.7 g, 0.210 mol) in 
acetone (800 ml) was refluxed for 24 hours. The mixture was filtered, the 
filtrate was concentrated on the rotary evaporator and the concentrate was 
partitioned between water and diethyl ether. The aqueous layer was 
extracted with diethyl ether and the combined extracts were washed with 
saturated sodium bicarbonate solution and brine and then dried 
(MgSO.sub.4) and concentrated. Flash chromatography on silica gel (elution 
with 20-50% diethyl ether in n-hexane) gave propyl (3-propyloxy)benzoate. 
Yield 3.031 g. 
.sup.1 H NMR (CDCl.sub.3): 1.03 (3H, t, J=7.4 Hz), 1.05 (3H, t, J=7.4 Hz), 
1.73-1.89 (4H, m), 3.97 (2H, t, J=6.6 Hz), 4.28 (3H, t, J=6.6 Hz), 7.09 
(1H, ddd, J=1.1, 2.8 and 8.3 Hz), 7.33 (1H, t, J=8.2 Hz), 7.56 (1H, dd, 
J=1.4 and 2.5 Hz), 7.63 (1H, m)ppm. 
To a suspension of LiAlH.sub.4 (680 mg, 17.9 mmol) in dry diethyl ether (60 
ml) at 0.degree. C. was added a solution of propyl (3-propyloxy)benzoate 
(2.948 g, 13.3 mmol), in diethyl ether (25 ml) dropwise over 20 minutes. 
After completion of the addition, the mixture was stirred for a further 1 
hour at 0.degree. C. The excess LiAlH.sub.4 was destroyed by the dropwise 
addition of methanol (2 ml), water (4 ml) and 10% sodium hydroxide 
solution (4 ml). The mixture was filtered through Celite and the organic 
layer was separated, dried (MgSO.sub.4) and concentrated to give the title 
compound as a clear oil. Yield 2.101 g (95%). 
.sup.1 H NMR (CDCl.sub.3): 1.04 (3H, t, J=6.9 Hz), 1.81 (2H, m), 3.94 (2H, 
t, J=6.5 Hz), 4.67 (2H, s), 6.81-6.94 (3H, m), 7.27 (1H, t, J=8.1 Hz)ppm. 
IR (thin film): 3340 cm.sup.-1 (broad). 
Description 4 
2-Iodo-3-propyloxybenzyl alcohol 
A suspension of 3-propyloxybenzyl alcohol (6.31 g, 38.0 mmol) in dry 
n-hexane (160 ml)/diethyl ether (21 ml) was stirred at -78.degree. C. 
under argon and treated with n-butyl lithium (52.2 ml of 1.6 M solution in 
hexanes, 83.5 mmol). After stirring at -78.degree. C. for 30 minutes, the 
cooling bath was removed and the mixture was stirred at room temperature 
for 3.5 hours. The solution was recooded to -78.degree. C. and a mixture 
of iodine in n-hexane (120 ml)/diethyl ether (20 ml) was added slowly. 
After completion of the addition, the mixture was allowed to reach room 
temperature and then stirred vigourously for 1 hour. Water (20 ml) was 
added cautiously to quench the reaction and the mixture was partitioned 
between ethyl acetate and 10% aqueous sodium thiosulfate solution. The 
product was extracted into ethyl acetate and the extracts were washed with 
10% aqueous sodium thiosulfate solution and water and then dried 
(MgSO.sub.4) and concentrated. Column chromatography on silica gel gave 
the title compound as a white solid. Yield 7.762 g (70%). m.p. 
75-75.5.degree. C. 
.sup.1 H NMR (CDCl.sub.3): 1.11 (3H, t, J=7.4 Hz), 1.87 (2H, m), 2.11 (1H, 
t, J=6.6 Hz, exchanges with D.sub.2 O), 4.00 (2H, t, J=6.3 Hz), 4.71 (2H, 
d, J=6.6 Hz, collapses to singlet with D.sub.2 O), 6.74 (1H, dd, J=1.4 and 
8.3 Hz), 7.06 (1H, m), 7.29 (1H, m)ppm. 
IR (KBr disc): 3280 cm.sup.-1 (broad). 
Analysis: C 41.41%, H 4.43%, calculated for C.sub.10 H.sub.13 IO.sub.2 C 
41.12%, H 4.49%. 
Description 5 
2-Benzyloxy-4-methoxyphenyl boronic acid 
To a stirred and gently refluxing suspension of magnesium powder (382 mg, 
15.7 mmol) in THF (10 ml) containing a few crystals of iodine, was added 
dropwise, a solution of 2-benzyloxy-1-bromo-4-methoxybenzene (WO 93/08799, 
4.39 g, 15.0 mmol) in THF (40 ml). After completion of the addition, the 
mixture was refluxed for 1.25 hours, cooled and then transferred via a 
canula to a stirred solution of trimethyl borate (3.11 g, 3.40 ml, 30.0 
mmol) in THF (25 ml) at -78.degree. C. The mixture was stirred at 
-78.degree. C. for 30 minutes and then the cooling bath was removed and 
stirring was continued at room temperature for a further 2 hours. The 
mixture was partitioned between diethyl ether and 1 N HCl (200 ml) and the 
product was extracted into diethyl ether. The extracts were washed with 
water, dried (MgSO.sub.4) and concentrated to give a yellow solid. 
Trituration with warm diethyl ether/n-hexane gave after drying the title 
compound as a cream solid. Yield 2.159 g (56%). 
.sup.1 H NMR (CDCl.sub.3): 3.83 (3H, s), 5.11 (2H, s), 5.57 (2H, s, 
exchanges with D.sub.2 O), 6.53-6.60 (2H, m), 7.33-7.47 (5H, m), 7.79 (1H, 
d, J=8.3 Hz)ppm. 
Description 6 
2-(2-Benzyloxy-4-methoxyphenyl)-3-propyloxybenzyl alcohol 
A mixture of 2-iodo-3-propyloxybenzyl alcohol (1.02 g, 3.48 mmol), 
2-benzyloxy-4-methoxyphenyl boronic acid (999 mg, 3.83 mmol), 
Pd(PPh.sub.3).sub.4 (200 mg, 0.173 mmol) and 2 M sodium carbonate solution 
(3.5 ml, 7.96 mmol) was refluxed in toluene (20 ml/ethanol (5 ml) under 
argon. After 5 hours a further 70 mg of boronic acid was added and 
refluxing was continued for a further 1 hour. The mixture was cooled, 
diluted with diethyl ether (200 ml) and washed successively with brine, 5% 
aqueous sodium hydroxide solution , water and brine and then dried 
(MgSO.sub.4) and concentrated. Purification by chromatography on silica 
gel gave the title compound as a colourless gum. Yield 1.072 g (81%). 
.sup.1 H NMR (CDCl.sub.3): 0.79 (3H, t, J=7.4 Hz), 1.51-1.64 (2H, m), 2.00 
(1H, dd, J=5.0 and 7.7 Hz, exchanges with D.sub.2 O), 3.81 (3H, s), 3.83 
(2H, m), 4.32 (1H, dd, J=7.7 and 12.1 Hz), 4.39 (1H, dd, J=4.8 and 12.2 
Hz), 4.92 (1H, d, J=12.1 Hz), 4.98 (1H, d, J=12.1 Hz), 6.59 (2H, m), 6.92 
(1H, dd, J=1.2 and 8.3 Hz), 7.04-7.37 (8H, series of m)ppm. 
IR (thin film): 3440 cm.sup.-1 (broad). 
MS (CI, ammonia): 396 (MNH.sub.4.sup.+), 378 (MNH.sub.4.sup.+ -H.sub.2 O), 
361 (MH.sup.+ -H.sub.2 O), HRMS 378.1831 (M.sup.+), C.sub.24 H.sub.26 
O.sub.4 requires 378.1831. 
Description 7 
2-(2-Hydroxy-4-methoxyphenyl)-3-propyloxybenzyl alcohol 
A mixture of the benzyl ether of Description 6 (717 mg) and 10% palladium 
on charcoal (250 mg) in ethanol (65 ml was shaken under 1 atmosphere of 
hydrogen. After 30 minutes, the catalyst was removed by filtration and the 
filtrate was concentrated and chromatographed on silica gel (elution with 
30-40% ethyl acetate in n-hexane) to give the title compound as a white 
solid. Yield 432 mg (79%). m.p. 101.5-103.degree. C. (chloroform). 
.sup.1 H NMR (CDCl.sub.3): 0.84 (3H, t, J=7.4 Hz), 1.64 (2H, m), 1.7 (1H, 
broad s, exchanges with D.sub.2 O), 3.83 (3H, s), 3.89 (2H, m), 4.45 (2H, 
s), 5.3 (1H, broad s, exchanges with D.sub.2 O), 6.57 (2H, m), 6.97 (2H, 
m), 7.19 (1H, d, J=7.2 Hz), 7.38 (1H, t, J=7.8 Hz)ppm. 
IR (KBr disc): 3435, 3180 cm.sup.-1. 
Analysis: C 70.97%, H 7.05%, calculated for C.sub.17 H.sub.20 O.sub.4 C 
70.81%, H 6.99%. 
MS (CI): 306 (MNH.sub.4.sup.+), 289 (MH.sup.+), 271 (MH.sup.+ -H.sub.2 O). 
Description 8 
Ethyl 5-methoxy-2-(2-formyl-6-propyloxyphenyl)phenoxy acetate 
A mixture of the diol of Description 7 (401 mg, 1.39 mmol) and sodium 
hydride (61 mg of 60% dispersion in mineral oil, 1.53 mmol) was stirred in 
dry DMF (10 ml) at room temperature under argon. After 20 minutes, ethyl 
bromoacetate (244 mg, 0.162 ml, 1.46 mmol) was added and stirring was 
continued at room temperature for a further 20 minutes prior to work-up. 
The mixture was quenched with 10% aqueous HCl and the product was 
extracted into ethyl acetate. The extracts were washed with water and 
brine and then dried (MgSO.sub.4) and concentrated. This product was 
stirred in dichloromethane (25 ml) with manganese dioxide (4 g) at room 
temperature for 3.5 hours. The mixture was filtered through Celite and the 
filtrate was concentrated and chromatographed on silica gel (elution with 
25% ethyl acetate in n-hexane) to give the title compound as a viscous 
oil. Yield 373 mg (72%). 
.sup.1 H NMR (CDCl.sub.3); 0.85 (3H, t, J=7.4 Hz), 1.22 (3H, t, J=7.1 Hz), 
1.64 (2H, m), 3.84 (3H, s), 3.89 (2H, t, J=6.5 Hz), 4.17 (2H, q, J=7.2 
Hz), 4.46 (1H, d, J=16.2 Hz, part of AB system), 4.53 (1H, d, J=16.2 Hz, 
part of AB system), 6.42 (1H, d, J=2.2 Hz), 6.62 (1H, dd, J=2.3 and 8.4 
Hz), 7.15-7.19 (2H, m), 7.40 (1H, dt, J=0.8 and 8.0 Hz), 7.60 (1H, dd, 
J=1.3 and 7.9 Hz), 9.78 (1H, d, J=0.8 Hz)ppm. 
IR (thin film): 1757, 1754 cm.sup.-1. 
Analysis: C 67.58%, H 6.65%, calculated for C.sub.21 H.sub.24 O.sub.6, C 
67.73%, H 6.50%. 
MS (CI): 390 (MNH.sub.4.sup.+), 373 (MH.sup.+). 
Description 9 
1-Bromo-2-methoxymethoxy-4-methoxybenzene 
To a solution of 1-Bromo-2-hydroxy-4-methoxybenzene (5.00 g, 24.60 mmol) in 
DMF was added 60% sodium hydride (1.97 g, 49.20 mmol) at 0.degree. C. 
under argon. The mixture was allowed to stirr at 0.degree. C. for 15 
minutes, then to it was added 90% bromomethyl methylether (4.10 g, 29.50 
mmol). After stirring for 1 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 (Na2SO4). Removal of the 
solvent afforded the title compound as an oil (6.5 g, quantitative yield). 
.sup.1 H NMR (400 MHz, CDCl3) .delta. 7.41 (d, 2H), 6.76 (d, 1H), 6.47 
(dd, 1H), 5.24 (s, 2H), 3.87 (s, 3H), 3.53 (s, 3H). 
Description 10 
2-Methoxymethoxy-4-methoxy boronic acid 
To a solution of 1-Bromo-2-methoxymethoxy-4-methoxybenzene (6.10 g, 24.63 
mmol) of in THF (100 mL) was added 1.6 M n-butyl lithium in hexane (15.4 
mL, 24.63 mmol) at -78.degree. C. under argon. The reaction allowed to 
stir at -78.degree. C. for 1 h, then quenched with water and extracted 
with ethyl acetate. The organic extract was washed with brine and dried 
(Na2SO4). Removal of the solvent under reduced pressure afforded the title 
compound as solid (4.50 g, 87%). .sup.1 H NMR (400 MHz, CDCl3) .delta. 
7.76 (d, 1H), 6.72 (d, 1H), 6.63 (dd, 1H), 5.75 (s, 2H), 5.30 (s, 2H), 
3.83 (s, 3H), 3.58 (s, 3H). 
Description 11 
2-Iodo-3-propyloxybenzaldehyde 
To a solution of 2-Iodo-3-propyloxybenzy alcohol (2.90 g, 9.93 mmol) in 
methylene chloride (100 mL) was added activated manganese dioxide (4.20 g, 
0.021 mmol) at room temperature under argon. After stirring at room 
temperature for 24 h the mixture was filtered and the filterate was 
concentrated. Flash chromatography of the residue (silica gel, 1:4 ethyl 
acetate/hexane) afforded the title compound as an oil (2.08 g, 86% based 
on recovered starting material). .sup.1 H NMR (400 MHz, CDCl3) .delta. 
10.2 (s, 1H), 7.50 (dd, J=1.3 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.02 (dd, 
J=1.2 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H), 1.92 (sextet, 2H), 1.13 (t, J=7.4 
Hz, 3H). 
Description 12 
1-Methoxy-3,4-methylenedioxybenzene 
To a solution of sesamol (10.00 g, 0.072 mol) in DMF (50 mL) was added 
sodium hydride (2.08 g, 0.087 mol) at room temperature under argon. After 
stirring for 1 h the mixture was treated with Iodomethane (13.50 mL, 0.22 
mo) and stirred for another 18 h. Upon the removal of the solvent the 
residue was extracted with ethyl acetate and washed with water, dried 
(Na2SO4) and concentrated to afford the title compound as a dark brown oil 
(10.50 g, 96%); .sup.1 H NMR (250 MHz, CDCl3) .delta. 6.70 (d, J=20 Hz, 
1H), 6.55 (d, 1H), 6.30 (dd, 1H), 5.88 (s, 2H), 3.90 (s, 3H); TLC Rf 0.72 
(silica gel, 1:1 ether:hexane). 
Description 13 
2-Methoxy-4,5-methylenedioxy benzaldehyde 
To a solution of phosphorous oxychloride (3.00 mL, 0.033 mol) in DMF (10 
mL) was added a solution of 1-methoxy-3,4-methylenedioxybenzene (2.00 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%): .sup.1 H NMR (250 MHz, CDCl3) 
.delta. 10.22 (s, 1H), 7.20 (s, 1H), 6.52 (s, 1H), 5.98 (s, 2H), 3.85 (s, 
3H); mp: 110.degree.l C. 
Description 14 
Diethyl 2-(4,5-methylenedioxy-1-methoxybenzyliden)-malonate 
A solution of the 2-methoxy-4,5-methylenedioxy benzaldehyde (16.00 g, 0.089 
mol), diethyl malonate (15.00 mL, 0.090 mol), piperidine (4.40 mL, 0.044 
mol) and acetic acid (2.50 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 (Na2SO4). After removing 
the solvent, flash chromatography of the residue (silica gel, 25% ethyl 
acetate/hexane) provided the title compound as a yellow solid (26.00 g, 
91%): .sup.1 H NMR (250 MHz, CDCl3) .delta. 8.50 (s, 1H), 7.45 (d, J=10 
Hz, 1H), 7.10 (d, J=15 Hz, 1H), 5.85 (s, 2H), 4.15 (q, 4H), 3.40 (s, 3H), 
1.20 (m, 6H); mp: 118.degree. C. 
Description 15 
Diethyl 2-(4,5-methylenedioxy-2-methoxybenzyl)-malonate 
To a solution of the diethyl 
2-(4,5-methylenedioxy-1-methoxybenylidene)-malonate (23.40 g, 0.073 mol) 
in ethanol (100 mL) was added sodium borohydride (2.80 g, 0.073 mol) and 
the mixture was stirred at room temperature for 5 h. The reaction was 
quenched with water and extracted with ethyl acetate (3.times.200 mL). The 
combined organic extracts were dried (Na2SO4) and evaporated to afford the 
title compound as an oil (20.30 g, 86%): .sup.1 H NMR (250 MHz, CDCl3) 
.delta. 7.45 (d, J=10 Hz, 1H), 7.20 (d, J=15 Hz, 1H), 5.85 (s, 2H), 4.22 
(m, 4H), 3.40 (s, 2H), 3.30 (s, 3H), 1.25 (m, 6H). 
Description 16 
Ethyl hydrogen 2-(4,5-methylenedioxy-2-methoxybenzyl)-malonate 
To a solution of the diethyl 
2-(4,5-methylenedioxy-2-methoxybenzyl)-malonate (20.00 g, 0.066 mol) of in 
ethanol (50 mL) was added a solution of potassium hydroxide (3.50 g, 0.066 
mol) in water (25 mL). The solution stirred at reflux for 6 h. After 
cooling 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 (Na2SO4) and concentrated to afford the title compound 
as a yellow solid (17.30 g, 89%): .sup.1 H NMR (400 MHz, CDCl3) .delta. 
10.20 (b, 1H), 6.68 (s, 1H), 6.50 (s, 1H), 5.90 (s, 2H), 4.15 (q, 2H), 
3.72 (s, 3H), 3.10 (dd, 2H), 1.20 (t, 3H); MS(ESI) m/e 297.0 [M+H].sup.+. 
Description 17 
2-(2-Methoxymethoxy-4-methoxy)phenyl-3-propyloxybenzaldehyde 
To a solution of 2-Methoxymethoxy-4-methoxy boronic acid (2.45 g, 11.60 
mmol) and 2-Iodo-3-proplyoxybenzaldehyde (2.24 g, 7.72 mmol) in 
benzene/ethyl acetate (20:4 ml respectivly) was added an aqueous solution 
of 0.2 M sodium carbonate (1g, 0.009 mol, in 4 ml H2O) followed by 
Tetrakis(triphenylphosphine)palladium (0) (0.45 g, 0.39 mmol, 5mol %). The 
reaction was allowed to stirr at reflux for 14 h. The mixture was cooled 
to room temperature then diluted with 1:1 ethyl acetate/hexane, washed 
with water, brine and dried (Na2SO4). After removing the solvent, flash 
chromatography of the residue (silica gel, 1:5 ethyl acetate/hexane) 
provided the title compound as a solid (2.2 g, 86%). .sup.1 H NMR (400 
MHz, CDCl3) .delta. 9.75 (s, 1H), 7.60 (dd, J=7.4 Hz, 1H), 7.40 (t, J=8.0 
Hz, 1H), 7.8 (dd, J=7.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 6.81 (d, J=2.4 
Hz, 1H), 6.64 dd, J=2.4 Hz, 1H), 5.02 JAB=6.8 Hz, .DELTA.=67 =30 Hz, 2H), 
3.88 (t, J=6.5 Hz, 2H), 3.85 (s, 3H), 3.29 (s, 3H), 1.64 (sextet, 2H), 
0.85 (t, J=7.4 Hz, 3H). 
Description 18 
Methyl-2-(bromomethyl)benzoate 
To a solution of methyl-2-methylbenzoate (3.00 g, 20.0 mmol) in carbon 
tetrachloride (15 mL) was added N-Bromosuccinimide (3.55 g, 20.00 mmol). 
The reaction was allowed to stirr at reflux for 3 h. The mixture was 
cooled and then partioned between 1:1 ethyl acetate/hexane and the combine 
organic extracts were washed with brine and dried (Na2SO4). Removal of the 
solvent under reduced pressure afforded the title compound as a yellowish 
liquid (4.70 g, quantitative yield). .sup.1 H NMR (400 MHz, CDCl3) .delta. 
7.98 (d, 1H), 7.54-7.35 (mm, 3H), 4.98 (s, 2H), 3.98 (s, 3H).