U.S. patent application number 09/901951 was filed with the patent office on 2002-01-03 for endothelin receptor antagonists.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Cousins, Russell Donovan, Elliott, John Duncan, Lago, Maria Amparo, Leber, Jack Dale, Peishoff, Catherine Elizabeth.
Application Number | 20020002177 09/901951 |
Document ID | / |
Family ID | 27490587 |
Filed Date | 2002-01-03 |
United States Patent
Application |
20020002177 |
Kind Code |
A1 |
Cousins, Russell Donovan ;
et al. |
January 3, 2002 |
Endothelin receptor antagonists
Abstract
Novel indane and indene derivatives are described which are
endothelin receptor antagonists.
Inventors: |
Cousins, Russell Donovan;
(Oxford, PA) ; Elliott, John Duncan; (Wayne,
PA) ; Lago, Maria Amparo; (Audubon, PA) ;
Leber, Jack Dale; (Doylestown, PA) ; Peishoff,
Catherine Elizabeth; (West Chester, PA) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
27490587 |
Appl. No.: |
09/901951 |
Filed: |
July 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09901951 |
Jul 10, 2001 |
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09574413 |
May 19, 2000 |
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6274737 |
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09574413 |
May 19, 2000 |
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09099373 |
Jun 18, 1998 |
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6087389 |
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09099373 |
Jun 18, 1998 |
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08336444 |
Nov 9, 1994 |
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5817693 |
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08336444 |
Nov 9, 1994 |
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PCT/US94/04603 |
Apr 26, 1994 |
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PCT/US94/04603 |
Apr 26, 1994 |
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08066818 |
Apr 27, 1993 |
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08066818 |
Apr 27, 1993 |
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PCT/US92/09427 |
Oct 29, 1992 |
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PCT/US92/09427 |
Oct 29, 1992 |
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07854195 |
Mar 20, 1992 |
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07854195 |
Mar 20, 1992 |
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07787870 |
Nov 5, 1991 |
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Current U.S.
Class: |
514/299 ;
514/381; 514/416; 514/464; 514/470; 514/520; 546/282.4; 548/252;
548/482; 549/446; 549/469; 558/410 |
Current CPC
Class: |
C07C 45/71 20130101;
C07C 45/71 20130101; C07F 9/65517 20130101; C07D 307/79 20130101;
C07C 69/734 20130101; C07C 69/757 20130101; C07D 405/08 20130101;
C07D 317/60 20130101; C07C 49/84 20130101; C07C 49/84 20130101;
C07C 69/738 20130101; C07D 405/12 20130101; C07C 62/32 20130101;
C07C 62/30 20130101; C07C 62/34 20130101 |
Class at
Publication: |
514/299 ;
514/381; 514/416; 514/470; 514/464; 514/520; 546/282.4; 548/252;
548/482; 549/446; 549/469; 558/410 |
International
Class: |
C07D 257/00; A61K
031/44; A61K 031/41; A61K 031/36; A61K 031/34; A61K 031/275 |
Claims
1. A compound of Formula (I): 20wherein: R.sub.1 is
--X(CH.sub.2).sub.nAr or --X(CH.sub.2).sub.nR.sub.8 or 21R.sub.2 is
hydrogen, Ar, C.sub.1-4 alkyl or (c); P.sub.1 is
--X(CH.sub.2).sub.nR.sub.8; P.sub.2 is --X(CH.sub.2).sub.nR.sub.8,
or --X--R.sub.9--Y; R.sub.3 and R.sub.5 are independently hydrogen,
R.sub.11, OH, C.sub.1-8alkoxy, S(O).sub.qR.sub.11,
N(R.sub.6).sub.2, Br, F, I, Cl, CF.sub.3, NHCOR.sub.6,
R.sub.13CO.sub.2R.sub.7, --X--R.sub.9--Y, or
--X(CH.sub.2).sub.nR.sub.8 wherein each methylene group within
--X(CH.sub.2).sub.nR.sub.8 may be unsubstituted or substituted by
one or two --(CH.sub.2).sub.nAr groups; R.sub.4 is hydrogen,
R.sub.11, OH, C.sub.1-5alkoxy, S(O).sub.qR.sub.11,
N(R.sub.6).sub.2, Br, F, I, Cl or NHCOR.sub.6 wherein the
C.sub.1-5alkoxy may be unsubstituted or substituted by OH, methoxy
or halogen; R.sub.6 is independently hydrogen or C.sub.1-4alkyl;
R.sub.7 is independently hydrogen, C.sub.1-10alkyl,
C.sub.2-10alkenyl or C.sub.2-8alkynyl, all of which may be
unsubstituted or substituted by one or more OH, N(R.sub.6)2,
CO2R12, halogen or XCl-5alkyl; or R.sub.7 is (CH2)nAr; R.sub.8 is
hydrogen, R11, CO2R7, CO2C(R11)2 O(CO)XR7, PO3(R7)2,
SO.sub.2NR.sub.7R.sub.11, NR.sub.7SO.sub.2R.sub.11,
CONR.sub.7SO.sub.2R.sub.11, SO.sub.3R.sub.7, SO.sub.2R.sub.7,
P(O)(OR.sub.7)R.sub.7, CN, --CO.sub.2(CH.sub.2).sub.mC(O-
)N(R.sub.6).sub.2, C(R.sub.11).sub.2N(R.sub.7).sub.2,
C(O)N(R.sub.6).sub.2, tetrazole or OR.sub.6; R.sub.9 is a bond,
C.sub.1-10alkylene, C.sub.1-10alkenylene, C.sub.1-10alkylidene,
C.sub.1-10alkynylene, 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.sub.6).sub.2, COOH or halogen; R.sub.10 is R.sub.3
or R.sub.4; R.sub.11 is hydrogen, Ar, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, all of which may be
unsubstituted or substituted by one or more OH, CH.sub.2OH,
N(R.sub.6).sub.2 or halogen; R.sub.12 is hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl or C.sub.2-7alkynyl; R.sub.13 is divalent Ar,
C.sub.1-10alkylene, C.sub.1-10alkylidene, C.sub.2-10alkenylene,
C.sub.2-10alkynylene, all of which may be unsubstituted or
substituted by one or more OH, CH.sub.2OH, N(R.sub.6).sub.2 or
halogen; X is (CH.sub.2).sub.n, O, NR.sub.6 or S(O).sub.q; Y is
CH.sub.3 or X(CH.sub.2).sub.nAr; Ar is: 22naphthyl, indolyl,
pyridyl, thienyl, 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.sub.3 or R.sub.4
groups; A is C.dbd.O, or (C(R.sub.6).sub.2)m; B is --CH.sub.2--or
--O--; Z.sub.1 and Z.sub.2 are independently hydrogen,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, OH,
C.sub.1-8alkoxy, S(O).sub.qC.sub.1-8alkyl, N(R.sub.6).sub.2, Br, F,
I, Cl, NHCOR.sub.6, --X--R.sub.9--Y, --X(CH.sub.2).sub.nR.sub.8,
phenyl, benzyl or C.sub.3-6cycloalkyl wherein the C.sub.1-8alkyl,
C.sub.2-8alkenyl or C.sub.2-8alkynyl may be optionally substituted
by COOH, OH, CO(CH.sub.2).sub.nCH.sub.3,
CO(CH.sub.2).sub.nCH.sub.2N(R.sub.6).sub.2, or halogen; or Z.sub.1
and Z.sub.2 together may be --O--A--O--on contiguous carbons;
Z.sub.3 is Z.sub.1 or --X--R.sub.9--Y; q is zero, one or two; n is
an integer from 0 to six; m is 1, 2 or 3;and the dotted line
indicates the optional presence of a double bond; or a
pharmaceutically acceptable salt thereof; provided that R.sub.2 is
not hydrogen when X is S(O).sub.q; when the optional double bond is
present there is only one R.sub.10 and there is no P.sub.1 and
P.sub.2 is not NR.sub.6R.sub.9Y; and if X-R.sub.2 is attached to
the double bond, X is not NR.sub.6; and if R.sub.1 is attached
directly to the double bond, R.sub.1 is not NR.sub.6Ar; when
R.sub.3, R.sub.5, Z.sub.1, Z.sub.2, or Z.sub.3 is
X(CH.sub.2).sub.nR.sub.8 and n is not 0, X is oxygen or NR.sub.6
when R.sub.8 is OR.sub.6 or CO.sub.2H; when R.sub.8 is
CO.sub.2C(R.sub.11).sub- .2O(CO)XR.sub.7 X is not S(O).sub.q; the
compound of Formula I is not (1RS)-1,3-diphenylindene-2-carboxylic
acid; (cis,cis)-(1RS,3SR)-1,3-diphe- nylindane-2-carboxylic acid;
(1RS)-3-[3-Methyl-1-phenyl-(1H)-ind-2-en-1-yl- ]propionic acid; or
(1RS)-2-[1,3-diphenyl-(1H)-ind-2-en-2-yl]ethanoic acid;
1,3-diphenyl-1-ethoxyindene-2-carboxylic acid;
1,2,3-triphenylindene; 1,3 diphenylindene;
1-(2,3-dimethyl-2-buten-yl)-1,- 3-diphenylindene;
1,3-diphenyl-2-methylindene; 1,3-diphenyl-2-methylindane- ;
1,3-diphenylindane; 5,6-dimethoxy-1,3-dimethoxyindene;
1,3-bis(4,5-dimethoxy-2-hydroxyphenyl)-5,6-dimethoxyindane;
1,3-bis(3,4-dimethoxyphenyl)-5,6-dimethoxyindane;
1,3-diphenyl-2-methoxyi- dene, 1,3-diphenyl-2-ethoxyindene,
5-fluoro-2-methyl-indene-3-acetic acid, methyl
1,3-diphenylindene-2-carboxylate, ethyl 1,3-diphenylindene-2-carbo-
xylate, or 2-cyano-1,3-diphenylindene.
2. A compound of claim 1 wherein R.sub.1 is X(CH.sub.2).sub.nAr,
(Ar is (a) or (b)), dihydrobenzofuranyl, benzodioxanyl, cyclohexyl,
or C.sub.1-4alkyl; R.sub.2 is a moiety of formula (a) or (b),
C.sub.1-4alkyl, indolyl or hydrogen; R.sub.3 and R.sub.5 are
independently hydrogen, OH, C.sub.1-5alkoxy, halogen,
--OC.sub.1-4alkyl phenyl, R.sub.13CO.sub.2R.sub.7, C.sub.1-4alkyl,
N(R.sub.6).sub.2, NH(CO)CH.sub.3, --X(CH.sub.2).sub.nRS,
--X--R.sub.9 --Y, pyridyl, phenyl or S(O)qC.sub.1-5alkyl; R.sub.4
is hydrogen, OH, C.sub.1-5alkoxy, halogen, C.sub.1-4alkyl,
N(R.sub.6).sub.2, NH(CO)CH.sub.3 or S(O)qC.sub.1-5alkyl; Z.sub.1,
Z.sub.2 and Z.sub.3 are independently X--R.sub.9--Y, benzyl,
hydrogen, OH, C.sub.1-5alkoxy, --N(R.sub.6).sub.2,
S(O).sub.qC.sub.1-8alkyl, NHCOR.sub.6, X(CH.sub.2).sub.nR.sub.8 or
halogen, or Z.sub.1 and Z.sub.2 together may be --O--A--O on
contiguous carbons; P.sub.1 and P.sub.2 are independently hydrogen,
CO.sub.2H, C(R.sub.6).sub.2CO.sub.2H or tetrazole; Ar is a moiety
of formula (a), or (b), phenyl, or pyridyl; and X is
(CH.sub.2).sub.nor oxygen.
3. A compound of claim 2 wherein R.sub.3 is hydrogen,
--X(CH.sub.2).sub.nR.sub.8 or R.sub.13CO.sub.2R.sub.7; R.sub.4 and
R.sub.5 are independently hydrogen, OH, C.sub.1-5alkoxy,
SC.sub.1-5alkyl, substituted phenyl, F, Br, C.sub.1-3alkyl or
NH.sub.2; Z.sub.1 and Z.sub.3 are hydrogen and Z.sub.2 is hydrogen,
OH, C.sub.1-5alkoxy, halogen, X(CH.sub.2).sub.nR.sub.8, NH.sub.2,
benzyl or NH(CO)CH.sub.3, or Z.sub.1 and Z.sub.2 together may be
O--A--O on contiguous carbons and R.sub.1, R.sub.2, P.sub.1,
P.sub.2, Ar and X are as defined in claim 2.
4. A compound of claim 3 wherein R.sub.1 is a moiety of formula (b)
and R.sub.2 is a moiety of formula (a) or (b); A is CH.sub.2, B is
--O--; there is no optional double bond; R.sub.1 and XR.sub.2 are
trans to P.sub.1; Z.sub.2 is hydrogen, OH, C.sub.1-5alkoxy or
--OCH.sub.2CH.sub.2CH.sub.3, Z.sub.1 is hydrogen; R.sub.3 is
hydrogen, XAr, X(CH.sub.2).sub.nCO.sub.2H,
X(CH.sub.2).sub.nCONR.sub.7SO.sub.2R.sub- .11,
X((CR.sub.6)).sub.nOR.sub.6, or CH.dbd.CHCO.sub.2H; R.sub.4 is
hydrogen, substituted phenyl pyridyl or pyrimidyl, or
C.sub.1-2alkoxy; R.sub.5, R.sub.10 and P.sub.2 are hydrogen; and
P.sub.1 is CO.sub.2H or --C(R.sub.6).sub.2CO.sub.2H.
5. A compound of claim 4 wherein R.sub.1 is a moiety of formula (b)
and R.sub.2 is a moiety of formula (a); A is CH.sub.2, B is --O--;
there is no optional double bond; R.sub.1 and XR.sub.2 are trans to
P.sub.1; X is a bond; Z.sub.1 and Z.sub.3 are hydrogen; Z.sub.2 is
hydrogen, OH, or C.sub.1-5alkoxy; R.sub.3 is hydrogen, OAr (where
Ar is (a), (b), pyridyl or pyrimidyl and A is CH.sub.2 and B is
--O-- and Ar may be substituted by CO.sub.2H,
O(CH.sub.2).sub.1-3CO.sub.2H), O(CH.sub.2).sub.1-3CONHSO.su-
b.2R.sub.11, (CH.sub.2).sub.0-4CO.sub.2H, (CH.sub.2).sub.0-3CONH
SO.sub.2 R.sub.11, or O((CR.sub.6).sub.2).sub.2-4 OH; R.sub.4 is
hydrogen, C.sub.1-2alkoxy, or phenyl, pyridyl or pyrimidyl, all of
which may be substituted by R.sub.3 or C.sub.1-2alkoky; R.sub.5,
R.sub.10 and P.sub.2 are hydrogen; and P.sub.1 is CO.sub.2H or
CH.sub.2CO.sub.2H.
6. A compound of claim 1 selected from the group consisting of:
(1RS, 2SR, 3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-
1-(3,4-methylene-dioxyphenyl)--
5-(prop-1-yloxy)-indane-2-carboxylic acid. (1RS, 2SR,
3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(2-methoxy-4,5-methylenedioxy-
phenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid; (1RS, 2SR,
3RS)-3-[2-[(2)-Carboxyeth-1-yloxy]-4-methoxyphenyl]-
1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;
(1RS, 2SR,
3SR)-3-[2-[(E)-2-Carboxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylen-
edioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid; (1RS, 2SR,
3SR)-3-[2-(2-Carboxyeth-1-yl)-4-methoxyphenyl]-1-(3,4-methylenedioxypheny-
l)-5-(prop-1-yloxy)indane-2-carboxylic acid; (+)(1S, 2R,
3S)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-
methoxyphenyl]-1-(3,4-methylened-
ioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate; (1RS, 2SR,
3RS)-3-[2-(3-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-
-5-(prop-1-yloxy)indane-2-carboxylic acid; (1RS, 2SR,
3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyph-
enyl)-5-(prop-1-yloxy)indane-2-carboxylate. (1RS, 2SR,
3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5--
(prop-1-yloxy)indan-2-yl acetic acid. (1RS, 2SR,
3RS)-3-[2-(2-Hydroxyeth-
1-yloxy)-(4-methoxyphenyl)]-i-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-
indan-2-yl acetic acid.
7. A compound of claim 1 which is:
(+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-met-
hoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxyl-
ic acid;
8. A compound of claim 1 which is:
(+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-met-
hoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxyl-
ic acid disodium salt;
9. A compound of claim 1 which is:
(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-ylox-
y)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2--
carboxylate;
10. A compound of claim 1 which is:
(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-ylo-
xy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-
-carboxylate hemiethylenediamine salt;
11. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
12. A method of antagonizing endothelin receptors which comprises
administering to a subject in need thereof, an effective amount to
antagonize endothelin receptors of a compound of claim 1.
13. 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.
14. A method of treating hypertension, renal failure or
cerebrovascular disease which comprises administering to a subject
in need thereof, an effective amount of a compound of claim 1.
15. 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
16. 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.
17. 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.
18. A method of treatment of migraine which comprises administering
to a subject in need thereof, an effective amount of a compound of
claim 1.
19. 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.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel indane and indene
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
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.
[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 ischernia (Nichols
etal. 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 Luischer, Circ 83: 701, 1991)
heart failure, proliferation of vascular smooth muscle cells,
(Takagi, Biochem & Biophvs. 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).
[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, 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) and endotoxin shock and other endotoxin
induced diseases (Biochem. Biophvs. Res. Commun., 161: 1220-1227,
1989, Acta Physiol. Scand. 137: 317-318, 1989) and inflammatory
skin diseases, (Clin Res. 41:451 and 484, 1993) and macular
degeneration.
[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., November 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.
[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, congestive
heart failure, 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.
SUMMARY OF THE INVENTION
[0014] This invention comprises indane and indene derivatives
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, stroke, cerebrovascular vasospasm, myocardial
ischemia, angina, heart failure, atherosclerosis, and as an adjunct
in angioplasty for prevention of restenosis and benign prostatic
hypertrophy.
[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 --X(CH.sub.2).sub.nAr or
--X(CH.sub.2).sub.nR.sub.8 or 2
[0019] R.sub.2 is hydrogen, Ar, C.sub.1-4alkyl or (c);
[0020] P.sub.1 is --X(CH.sub.2).sub.nR.sub.8;
[0021] P.sub.2 is --X(CH.sub.2).sub.nR.sub.8, or
--X--R.sub.9--Y;
[0022] R.sub.3 and R.sub.5 are independently hydrogen, R.sub.11,
OH, C.sub.1-8alkoxy, S(O).sub.qR.sub.11, N(R.sub.6).sub.2, Br, F,
I, Cl, CF.sub.3, NHCOR.sub.6, R.sub.13CO.sub.2R.sub.7,
--X--R.sub.9--Y, or --X(CH.sub.2).sub.nR.sub.8 wherein each
methylene group within --X(CH.sub.2).sub.nR.sub.8 may be
unsubstituted or substituted by one or two --(CH.sub.2).sub.nAr
groups;
[0023] R.sub.4 is hydrogen, R.sub.11, OH, C.sub.1-5alkoxy,
S(O).sub.qR.sub.11, N(R.sub.6).sub.2, Br, F, I, Cl or NHCOR.sub.6
wherein the C.sub.1-5alkoxy may be unsubstituted or substituted by
OH, methoxy or halogen;
[0024] R.sub.6 is independently hydrogen or C.sub.1-4alkyl;
[0025] R.sub.7 is independently hydrogen, C.sub.1-10alkyl,
C.sub.2-10alkenyl or C.sub.2-8alkynyl, all of which may be
unsubstituted or substituted by one or more OH, N(R.sub.6).sub.2,
CO2R12, halogen or XC1-5alkyl; or R.sub.7 is (CH2).sub.nAr;
[0026] R.sub.8 is hydrogen, R11, CO2R7, CO2C(R11)2 O(CO)XR7,
PO3(R7)2, SO.sub.2NR.sub.7R.sub.11, NR.sub.7SO.sub.2R.sub.11,
CONR.sub.7SO.sub.2R.sub.11, SO.sub.3R.sub.7, SO.sub.2R.sub.7,
P(O)(OR.sub.7)R.sub.7, CN,
--CO.sub.2(CH.sub.2).sub.mC(O)N(R.sub.6).sub.2- ,
C(R.sub.11).sub.2N(R.sub.7).sub.2, C(O)N(R.sub.6).sub.2, tetrazole
or OR.sub.6;
[0027] R.sub.9 is a bond, C.sub.1-10alkylene, C.sub.1-10alkenylene,
C.sub.1-10alkylidene, C.sub.1-10alkynylene, 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.sub.6).sub.2, COOH or
halogen;
[0028] R.sub.10 is R.sub.3or R.sub.4;
[0029] R.sub.11 is hydrogen, Ar, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, all of which may be unsubstituted or substituted
by one or more OH, CH.sub.2OH, N(R.sub.6).sub.2 or halogen;
[0030] R.sub.12 is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-7alkynyl;
[0031] R.sub.13 is divalent Ar, C.sub.1-10alkylene,
C.sub.1-10alkylidene, C.sub.2-10alkenylene, C.sub.2-10alkynylene,
all of which may be unsubstituted or substituted by one or more OH,
CH.sub.2OH, N(R.sub.6).sub.2 or halogen;
[0032] X is (CH.sub.2).sub.n, O, NR.sub.6 or S(O).sub.q;
[0033] Y is CH.sub.3 or X(CH.sub.2).sub.nAr;
[0034] Ar is: 3
[0035] naphthyl, indolyl, pyridyl, thienyl, 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.sub.3 or R.sub.4 groups;
[0036] A is C=O, or (C(R.sub.6).sub.2)m;
[0037] B is --CH.sub.2- or --O--;
[0038] Z.sub.1 and Z.sub.2 are independently hydrogen,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, OH,
C.sub.1-8alkoxy, S(O).sub.qC.sub.1-8alkyl, N(R.sub.6).sub.2, Br, F,
I, Cl, NHCOR.sub.6, --X--R.sub.9--Y, --X(CH.sub.2).sub.nR.sub.8,
phenyl, benzyl or C.sub.3-6cycloalkyl wherein the C.sub.1-8alkyl,
C.sub.2-8alkenyl or C.sub.2-8alkynyl may be optionally substituted
by COOH, OH, CO(CH.sub.2).sub.nCH.sub.3,
CO(CH.sub.2).sub.nCH.sub.2N(R.sub.6).sub.2, or halogen; or Z.sub.1
and Z.sub.2 together may be --O--A--O-- on contiguous carbons;
[0039] Z.sub.3 is Z.sub.1 or --X--R.sub.9--Y;
[0040] q is zero, one or two;
[0041] n is an integer from 0 to six;
[0042] m is 1, 2 or 3;and the dotted line indicates the optional
presence of a double bond; or a pharmaceutically acceptable salt
thereof; provided that
[0043] R.sub.2 is not hydrogen when X is S(O).sub.q;
[0044] when the optional double bond is present there is only one
R.sub.10 and there is no P.sub.1 and P.sub.2 is not
NR.sub.6R.sub.9Y; and if X--R.sub.2 is attached to the double bond,
X is not NR.sub.6; and if R.sub.1 is attached directly to the
double bond, R.sub.1 is not NR.sub.6AR;
[0045] when R.sub.3, R.sub.5, Z.sub.1, Z.sub.2, or Z.sub.3 is
X(CH.sub.2).sub.nR.sub.8 and n is not 0, X is oxygen or NR.sub.6
when R.sub.8 is OR.sub.6 or CO.sub.2H;
[0046] when R.sub.8 is CO.sub.2C(R.sub.11).sub.2O(CO)XR.sub.7, X is
not S(O).sub.q;
[0047] the compound of Formula I is not
(1RS)-1,3-diphenylindene-2-carboxy- lic acid;
(cis,cis)-(1RS,3SR)-1,3-diphenylindane-2-carboxylic acid;
(1RS)-3-[3-Methyl-1-phenyl-(1H)-ind-2-en-1-yl] propionic acid; or
(1RS)-2-[1,3-diphenyl-(1H)-ind-2-en-2-yl]ethanoic acid;
1,3-diphenyl-1-ethoxyindene-2-carboxylic acid;
1,2,3-triphenylindene; 1,3 diphenylindene;
1-(2,3-dimethyl-2-buten-yl)-1,3-diphenylindene;
1,3-diphenyl-2-methylindene; 1,3-diphenyl-2-methylindane;
1,3-diphenylindane; 5,6-dimethoxy-1,3-dimethoxyindene;
1,3-bis(4,5-dimethoxy-2-hydroxyphenyl)-5,6-dimethoxyindane;
1,3-bis(3,4-dimethoxyphenyl)-5,6-dimethoxyindane;
1,3-diphenyl-2-methoxyi- dene, 1,3-diphenyl-2-ethoxyindene,
5-fluoro-2-methyl-indene-3-acetic acid, methyl
1,3-diphenylindene-2-carboxylate, ethyl 1,3-diphenylindene-2-carbo-
xylate, or 2-cyano-1,3-diphenylindene.
[0048] Also included in the invention are pharmaceutically
acceptable salt complexes. Preferred are the ethylene diamine,
sodium, potassium, calcium and ethanolarnine salts.
[0049] The term alkylene is a divalent alkyl group in which the
bonds are on two different carbon atoms; alkylidene is a divalent
alkyl group in which the bonds are on the same carbon atom;
alkenylene is a divalent alkene group in which the bonds may be on
any carbon atom; alkynylene is a divalent alkynyl group in which
the bonds may be on any carbon atom.
[0050] All alkyl, alkenyl, alkynyl, alkoxy, alkylene, alkylidene,
alkenylene and alkynylene groups may be straight or branched. The
term "halogen" is used to mean iodo, fluoro, chloro or bromo. Alkyl
groups may be substituted by one or more halogens up to
perhalocenation.
[0051] The compounds of the present invention may contain one or
more asymmetric 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.
[0052] Preferred compounds are those wherein R.sub.1 is
X(CH.sub.2).sub.nAr, (Ar is (a) or (b)), dihydrobenzofuranyl,
benzodioxanyl, cyclohexyl or C.sub.1-4alkyl; R.sub.2 is a moiety of
formula (a) or (b), C.sub.1-4alkyl, indolyl or hydrogen; R.sub.3
and R.sub.5 are independently hydrogen, OH, C.sub.1-5alkoxy,
halogen, --OC.sub.1-4alkyl phenyl, R.sub.13CO.sub.2R.sub.7,
C.sub.1-4alkyl, N(R.sub.6).sub.2, NH(CO)CH.sub.3,
--X(CH.sub.2).sub.nR.sub.8, --X--R.sub.9--Y pyridyl, phenyl or
S(O).sub.pC.sub.1-5alkyl; R.sub.4 is hydrogen, OH, C.sub.1-5alkoxy,
halogen, C.sub.1-4alkyl, N(R.sub.6).sub.2, NH(CO)CH.sub.3 or
S(O).sub.pC.sub.1-5alkyl; Z.sub.1, Z.sub.2 and Z.sub.3 are
independently XR.sub.9Y, benzyl, hydrogen, OH, C.sub.1-5alkoxy,
--N(R.sub.6).sub.2, S(O)qC.sub.1-8alkyl, NHCOR.sub.6,
X(CH.sub.2).sub.nR.sub.8 or halogen, or Z.sub.1 and Z.sub.2
together may be --O--A--O on contiguous carbons; P.sub.1 and
P.sub.2 are independently hydrogen, CO.sub.2H,
C(R.sub.6).sub.2CO.sub.2H or tetrazole; Ar is a moiety of formula
(a) or (b), phenyl, or pyridyl; X is (CH.sub.2).sub.n or
oxygen.
[0053] More preferred are compounds wherein R.sub.3 is hydrogen,
--X(CH.sub.2).sub.nR.sub.8 or R.sub.13CO.sub.2R.sub.7; R.sub.4 and
R.sub.5 are independently hydrogen, OH, C.sub.1-5alkoxy,
SC.sub.1-5alkyl, substituted phenyl, F, Br, C.sub.1-3alkyl or
NH.sub.2; Z.sub.1 and Z.sub.3 are hydrogen and Z.sub.2 is hydrogen,
OH, C.sub.1-5alkoxy, halogen, X(CH.sub.2).sub.nR.sub.8, NH.sub.2,
benzyl, NH(CO)CH.sub.3, or Z.sub.1 and Z.sub.2 together may be
O--A--O on contiguous carbons and R.sub.1, R.sub.2, P.sub.1,
P.sub.2, Ar and X are as above for preferred compounds.
[0054] Most preferred are compounds wherein R.sub.1 is (b) and
R.sub.2 is (a) or (b); A is CH.sub.2, B is --O--; there is no
optional double bond; R.sub.1 and XR.sub.2 are trans to P.sub.1;
Z.sub.2 is hydrogen, OH, C.sub.1-5alkoxy, or
--OCH.sub.2CH.dbd.CH.sub.2, Z.sub.1 is hydrogen; R.sub.3 is XAr,
hydrogen, X(CH.sub.2).sub.nCOOH, X(CH.sub.2).sub.nCONR.su-
b.7SO.sub.2R.sub.11, X[(CR.sub.6).sub.2].sub.nOR.sub.6 or
CH.dbd.CHCO.sub.2H; R.sub.4 is hydrogen, substituted phenyl,
pyridyl or pyrimidyl, or C.sub.1-2alkoxy; R.sub.5, R.sub.10 and
P.sub.2 are hydrogen, and P.sub.1 is CO.sub.2H or
C(R.sub.6).sub.2CO.sub.2H.
[0055] Especially preferred are compounds wherein R.sub.1 is (b)
and R.sub.2 is (a); A is CH.sub.2, B is --O--; there is no optional
double bond; R.sub.1 and XR.sub.2 are trans to P.sub.1; X is a
bond; Z.sub.1 and Z.sub.3 are hydrogen; Z.sub.2 is hydrogen, OH or
C.sub.1-5alkoxy; R.sub.3 is hydrogen, OAr (where Ar is (a), (b),
pyridyl or pyrimidyl and A is CH.sub.2 and B is --O-- and Ar may be
substituted by CO.sub.2H), O(CH.sub.2).sub.1-3CO.sub.2H,
O(CH.sub.2).sub.1-3CONHSO.sub.2R.sub.11,
(CH.sub.2).sub.0-4CO.sub.2H, (CH.sub.2).sub.0-3CONH
SO.sub.2R.sub.11, or O[(CR.sub.6).sub.2].sub.2-4 OH; R.sub.4 is
hydrogen, C.sub.1-2alkoxy, or phenyl, pyridyl or pyrimridyl all of
which may be substituted by R.sub.3 or C.sub.1-2alkoxy; R.sub.5,
R.sub.10 and P.sub.2 are hydrogen; and P.sub.1 is CO.sub.2H or
CH.sub.2CO.sub.2H.
[0056] Especially preferred compounds are the following:
[0057] (1RS
,2SR,3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylen-
edioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid;
[0058] (+)(1S
,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylen-
edioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid;
[0059] (+)(1S
,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylen-
edioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid disodium
salt;
[0060]
(1RS,2SR,3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(2-methoxy-4,5-
-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic
acid;
[0061]
(1RS,2SR,3RS)-3-[2-(2-Carboxyeth-1-yloxy]-4-methoxyphenyl]-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid;
[0062]
(1RS,2SR,3SR)-3-[2-[(E)-2-Carboxyethen-1-yl]-4-methoxyphenyl]-1-(3,-
4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid;
[0063]
(1RS,2SR,3SR)-3-[2-(2-Carboxyeth-1-yl)-4-methoxyphenyl]-1-(3,4-meth-
ylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid;
[0064]
(1RS,2SR,3RS)-3-[2-(3-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid;
[0065]
(+)(1S,2R,3S)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1--
(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;
[0066]
(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;
[0067] (1RS,2S
R,3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4--
methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;
[0068]
(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
hemiethylenediamine salt;
[0069]
(1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylene-
dioxyphenyl)-5-(prop-1-yloxy)indane-2-yl-acetic acid.
[0070]
(1RS,2SR,3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-yl acetic acid
[0071] The present invention provides compounds of Formula (I)
above 4
[0072] which can be prepared by a process which comprises:
[0073] a) reacting a compound of Formula (2) wherein X is
C.sub.1-5alkyl 5
[0074] with a substituted benzaldehyde or aldehyde of Formula
(3).
D-CHO (3)
[0075] wherein D is Ar or (c) as defined in Formula I, in a
suitable solvent such as benzene with a catalyst such as
piperidinium acetate at reflux to provide a compound of Formula
(4). 6
[0076] Cyclization of compound (4) in the presence of a suitable
Lewis acid such as titanium tetracholoride or aluminum chloride or
alternatively when Z.sub.1 is 3--OR (meta)(where R is
C.sub.1-5alkyl, or benzyl), trifluoroacetic acid, provides an
indanone of the Formula (5). 7
[0077] Dehydrogenation with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an appropriate solvent
or alternatively bromination with pyridinium hydrobromide
perbromide in dichloromethane followed by treatment with
1,5-diazabicyclo[4,3,0]non-5-ene provides indenones of Formula (6).
8
[0078] b) Alternatively, a compound of Formula 6 wherein Z.sub.1,
Z.sub.2 and Z.sub.3 are hydrogen and 9
[0079] can be prepared by treatment of 2-bromobenzoic acid with two
equivalents of n-butyllithium in a solvent such as tetrahydrofuran
under argon at -78.degree. C. followed by the addition of an acid
chloride of Formula (7): 10
[0080] provides a compound of Formula (8): 11
[0081] Treatment of compounds of type (8) with thionyl chloride at
reflux gives an acid chloride which can be isolated by
concentration under reduced pressure. This acid chloride can then
be treated with diethyl magnesium malonate in a solvent such as
ether to give a compound of Formula (9): 12
[0082] Reaction of a compound of type (9) at reflux with 5% aqueous
sodium carbonate gives compounds of Formula (10): 13
[0083] c) Treatment of an indenone of Formula (11): 14
[0084] wherein Z.sub.1, Z.sub.2, Z.sub.3 and R.sub.1 are as defined
for formula I or a group convertable to them, with an
organomagnesium compound of Formula (12) wherein R.sub.2 is defined
for
R.sub.2(CH.sub.2).sub.nMgBr (12)
[0085] Formula I or a group convertable to it, in a suitable
solvent provides compounds of Formula (13): 15
[0086] Saponification of compounds of Formula (13) using sodium
hydroxide in aqueous methanol followed by reduction with
triethylsilane and boron trifluoride etherate in a suitable solvent
such as dichloromethane at 0.degree. C. affords racemic compounds
of Formula (14). 16
[0087] Conjugate addition of nucleophiles to an ester derived from
Formula (14), followed by saponification affords compounds of
Formula (I) having an R.sub.10 other than hydrogen. Re-introduction
of a double bond into an ester derived from such acids followed by
conjugate addition of another nucleophilic species and subsequent
saponification affords compounds of Formula (1) in which neither
R.sub.10 substituent is hydrogen.
[0088] Reduction of compounds of Formula (13) with triethylsilane
and boron trifluoride etherate in a suitable solvent such as
dichloromethane at 0.degree. C. followed by hydrogenation with
hydrogen gas under pressure at approximately 60 psi in the presence
of a suitable catalyst such as 10% palladium on charcoal affords
compounds of Formula (15): 17
[0089] Alkylation or acylation of the ester enolate derived from
Formula (15) affords compounds wherein P.sub.1 and P.sub.2 are as
defined in Formula (I).
[0090] Alternatively, hydrogenation of compounds of Formula (13)
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 methanol containing
1-5% acetic acid affords compounds of Formula (15). Treatment of
these compounds with a base such as sodium hydroxide in a suitable
solvent such as aqueous ethanol provides racemic compounds of
Formula (16): 18
[0091] wherein Z.sub.1, Z.sub.2 and Z.sub.3 are hydrogen;
R.sub.1=R.sub.2; and n is 0. Treatment of compounds of Formula (13)
with triethylsilane and boron trifluoride etherate in a suitable
solvent such as dichloromethane at 0.degree. C. followed by
reaction with samarium II iodide in a suitable solvent such as
tetrahydrofuran and then saponification, provides compounds of
Formula (17) 19
[0092] With appropriate manipulation and protection of any chemical
functionalities, synthesis of the remaining compounds of the
Formula (I) is accomplished by methods analogous to those above and
to those described in the Experimental section.
[0093] 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.
[0094] Compounds of Formula (1) 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.
[0095] Compounds of Formula (1) 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.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] 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.
[0100] 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.
[0101] 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/Kg, of a compound of Formula (1) 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 5.0% of a compound of Formula
(I).
[0102] 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.
[0103] No unacceptable toxicological effects are expected when
compounds of the invention are administered in accordance with the
present invention.
[0104] The biological activity of the compounds of Formula (I) are
demonstrated by the following tests:
[0105] I. Binding Assay
[0106] A) Membrane Preparation (Rat cerebellum or kidney
cortex)
[0107] 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 xg for
10 minutes at 4.degree. C. The supernatant was removed and
centrifuged at 40,000 xg 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 micrograms of protein for each tube for
cerebellum and kidney cortex in the binding assay.
[0108] 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 5mM 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 xg for 10 min. at 4.degree. C.
The supernatant was removed and centrifuged at 40,000 xg for 30
min. at 4.degree. C. The resulting pellet was resuspended as
explained above for cerebellum and kidney cortex. Approximately 10
micrograms of membrane protein was used for each tube in binding
experiments.
[0109] B) CHO Cell Membrane Preparation
[0110] CHO cells stably transfected with human ETA and ETB
receptors were grown in 245 mm.times.245 mm tissue culture plates
in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10%
fetal bovine serum (FBS). The confluent cells were washed with DPBS
(Dulbecco's phosphate buffered saline) containing protease
inhibitor cockatil (5 mM EDTA, 0.5 mM PMSF, 5 ug/ml leupeptin, and
0.1 U/ml aprotinin) and scraped in the same buffer. After
centrifugation at 800 xg, the cells were lysed by freezing in
liquid nitrogen and thawing on ice followed by homogenization (30
times using glass dounce homogenizer) in lysis buffer containing 20
mM Tris HCl, pH 7.5 and the protease inhibitor cocktail. After an
initial centrifugation at 800 xg for 10 min to remove unbroken
cells and nuclei, the supernatants were centrifuged at 40,000 xg
for 15 min and the pellet was resuspended in 50 mM Tris HCl, pH 7.5
and 10 mM MgCl.sub.2 and stored in small aliquots at -70.degree. C.
after freezing in liquid N.sub.2. Protein was determined using BCA
method and bovine serum albumin as the standard.
[0111] C) [.sup.125I]ET-1 Binding Protocol
[0112] .sup.125I]ET-1 binding to membranes from rat cerebellum (2-5
mg protein/assay tube) or kidney cortex (3-8 micrograms
protein/assay tube) or CHO cell membranes (containing 4-6 and 1-2
micrograms of membrane protein for ETA and ETB receptors,
respectively) 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 microliters. Membrane p rotein
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%. IC.sub.50's for the compounds of this invention range from
0.01 nm to 50 uM.
[0113] II. In Vitro Vascular Smooth Muscle Activity
[0114] 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; KC1, 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.
[0115] 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.sub.b) of competitive antagonists were
determined by the standard method of Arunlakshana and Schild. The
potency range for compounds of this invention range from 0.01 nM to
50 uM.
[0116] The following examples are illustrative and are not limiting
of the compounds of this invention.
EXAMPLE 1
(1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylic
acid
[0117] a) Ethyl
(1RS)[1-Hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carb-
oxylate. To dry magnesium turnings (0.88 g, 36 mmol) under an argon
atmosphere was added, portionwise, a solution of p-bromoanisole
(4.5 ml, 36 mmol) in 5% THF/ Et.sub.2O (37 ml). The resulting
p-methoxyphenyt magnesium bromide solution was added to a solution
of ethyl 1-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in
Et.sub.2O (300 ml) under an argon atmosphere at 0.degree. C. The
resulting mixture was allowed to warm to room temperature and was
stirred for 10 min. The mixture was partitioned between 3M HCl (100
ml) and EtOAc (200 ml). The organic extract was washed successively
with H.sub.2O, aqueous NaHCO.sub.3, H.sub.2O and saturated aqueous
NaCl and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo
to provide a yellow oil which was treated with Et.sub.2O/ hexanes.
The solid which formed was collected by filtration (3.47 g). The
filtrate was concentrated under reduced pressure and purified by
flash chromatography. The material which was isolated was treated
with Et.sub.2O/ hexanes, and the additional solid which formed
(1.76 g, 75% total yield) was collected by filtration to afford the
title compound.
[0118] b) Ethyl
(RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylate. To a
solution of ethyl (1RS)
[1-hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-- 2-carboxylate
(4.65 g, 12.0 mmol) in CH.sub.2Cl.sub.2 (40 ml) at 0.degree. C.
under an argon atmosphere was added triethylsilane (2.34 ml, 14.6
mmol), followed by boron trifluoride etherate (8.8 ml, 71 mmol).
The reaction mixture was allowed to warm to room temperature and
stirred for 10 min, at which time was added slowly 3M HCl (50 ml).
The mixture was extracted with EtOAc (150 ml). The organic extract
was washed successively with H.sub.2O, aqueous NaHCO.sub.3,
H.sub.2O and saturated aqueous NaCl and dried. The solvent was
removed in vacuo, and the residue was purified by flash
chromatography on silica gel, eluting with 10% EtOAc/ hexanes to
provide the title compound (4.2 g, 95%) as a mixture of .DELTA.1
and .DELTA.2 double bond isomers.
[0119] c) Ethyl
(1RS,2SR,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxy- late.
To a solution of ethyl
(RS)-1-(4-methoxyphenyl)-3-phenylindene-2-car- boxylate (5.75 g, 15
mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon
(600 mg). The resulting suspension was stirred under an atmosphere
of H.sub.2 for 1 d, then was filtered through a pad of Celite. The
filtrate was concentrated under reduced pressure to afford the
title compound, which was used without further purification.
[0120] d)
(1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylic acid.
To a solution of ethyl (1RS
,2SR,3SR)-1-(4-methoxyphenyl)-3-phenyli- ndane-2-carboxylate, (5.5
g, 14.8 mmol) in EtOH (70 ml) was added 5M NaOH (9 ml, 45 mmol).
The resulting mixture was stirred under an argon atmosphere for 1
d, at which time H.sub.2O (70 ml) was added. The mixture was
concentrated under reduced pressure. The aqueous residue was
extracted with Et.sub.2O, and the Et.sub.2O extracts were
discarded. The aqueous phase was acidified with 6M HCl and
extracted several times with EtOAc. The combined EtOAc extracts
were washed successively with H.sub.2O and saturated aqueous NaCl
and dried. The solvent was removed in vacuo to provide an oily
residue which crystallized upon standing. The solid material was
recrystallized from EtOAc/ hexanes to afford the title compound
(4.25 g, 83%); m.p. 164 -166.degree. C. .sup.1H NMR (CDCl.sub.3):
.delta.7.35-7.18 (m, 9H); 6.92-6.88 (m, 4H); 4.68 (d, 1H, J=10 Hz);
4.64 (d, 1H, J=10 Hz); 3.81 (s, 3H); 3.34 (t, 1H, J=10 Hz). MS: 345
[(M+H)+]. Anal. Calc. for C.sub.23H.sub.20O.sub.3: C, 80.21; H,
5.85. Found C, 80.21; H 6.03.
EXAMPLE 2
(trans, trans)-1,3-Di(4-methoxyphenyl)-indane-2-carboxylic acid
[0121] a) Ethyl 2-Benzoyl-3-(4-hydroxyphenyl)propenoate. To a
solution of 4-hydroxybenzaldehyde (31.7 g, 0.26 mol) and ethyl
benzoylacetate (45.5 ml, 0.26 mol) in EtOH (45 ml) under an argon
atmosphere was added piperidine (2.6 ml, 0.026 mol) and acetic acid
(3 drops). After stirring at room temperature overnight, the
resulting solid mixture was treated with hot EtOH (700 ml), and
then allowed to cool. The crystals which formed were collected by
filtration to afford the title compound (61.0 g, 79%).
[0122] b) Ethyl
(2RS,3SR)-3-(4-Hydroxyphenyl)-1-oxoindane-2-carboxylate. To a
mixture of ethyl 2-benzoyl-3-(4-hydroxyphenyl)propenoate (0.50 g,
1.7 mmol) in CH.sub.2Cl.sub.2 (15 ml) at 0.degree. C. under an
argon atmosphere was added titanium tetrachloride (0.93 ml, 8.3
mmol). The resulting mixture was allowed to stir at room
temperature overnight. The reaction was slowly quenched with 3M
HCl, then partitioned between EtOAc (50 ml) and 3M HCl. The aqueous
phase was extracted with EtOAc, and the combined organic extracts
were washed successively with H.sub.2O and saturated aqueous NaCl,
and dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo, and
the solid residue was recrystallized from EtOAc/hexanes to afford
the title compound (410 mg, 82%).
[0123] c) Ethyl
(2RS,3SR)-3-(4-t-Butyldimethylsiloxyphenyl)-1-oxoindane-2--
carboxylate. To a solution of ethyl
(2RS,3SR)-3-(4-hydroxyphenyl)-1-oxoind- ane-2-carboxylate (3.0 g,
10.2 mmol) in DMF (10 ml) under an argon atmosphere were added
imidazole (1.72 g, 25.3 mmol) and t-butyldimethylchloro-silane
(1.82 g, 12.1 mmol). The resulting mixture was allowed to stir at
room temperature for 3 d, then was poured into dilute aqueous HCl
and extracted with EtOAc (2x). The combined organic extracts were
washed successively with H.sub.2O aqueous NaHCO.sub.3, H.sub.2O and
saturated aqueous NaCl and dried. The solvent was removed in vacuo
to provide the title compound (5.40 g) which was used without
further purification.
[0124] d) Ethyl
3-(4-t-Butyldimethylsiloxyphenyl)-1-oxoindene-2-carboxylat- e. To a
solution of ethyl (2RS,3SR)-3-(4-t-butyldimethylsiloxyphenyl)-1-ox-
oindane-2-carboxylate (130 mg, 0.32 mmol) in CH.sub.2Cl.sub.2 (3
ml) under an argon atmosphere was added
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35 mmol). The
resulting mixture was stirred for 2.5 h. Aqueous NaHSO.sub.3 and
EtOAc were added, and the mixture was stirred for 5 min. The
aqueous phase was separated and extracted with EtOAc, and the
combined organic extracts were washed successively with aqueous
NaHCO.sub.3, H.sub.2O and saturated aqueous NaCl and dried. The
solvent was removed in vacuo, and the residue was purified by flash
chromatography on silica gel to afford the title compound (110 mg,
85%).
[0125] e) Ethyl
(1RS)-3-(4-t-Butyldimethylsiloxyphenyl)-1-hydroxy-1-(4-met-
hoxyphenyl)indene-2-carboxylate. To dry magnesium turnings (119 mg,
4.9 mmol) under an argon atmosphere was added, portionwise, a
solution of p-bromoanisole (0.61 ml, 4.9 mmol) in 9: 1 Et.sub.2O/
THF (10 ml). The resulting p-methoxyphenyl magnesium bromide
solution was added to a solution of ethyl
3-(4-t-butyldimethylsiloxyphenyl)-1-oxoindene-2-carboxy- late (1.00
g, 2.5 mmol) in Et.sub.2O (60 ml) under an argon atmosphere at
0.degree. C. The resulting mixture was allowed to warm to room
temperature and was stirred for 5 min. The mixture was partitioned
between 3M HCl and EtOAc. The organic extract was washed
successively with H.sub.2O aqueous NaHCO.sub.3, H.sub.2O and
saturated aqueous NaCl and dried. The solvent was removed in vacuo
to provide the title compound (1.47 g) which was used without
further purification.
[0126] f) Ethyl
(RS)-1-hydroxy-(4-t-Butyldimethylsiloxyphenyl)-3-(4-methox-
yphenyl)indene-2-carboxylate. To a solution of ethyl
(1RS)-3-(4-t-butyldimethylsiloxyphenyl)-1-hydroxy-1-(4-methoxyphenyl)inde-
ne-2-carboxylate (2.5 mmol, prepared above) in CH.sub.2Cl.sub.2 (10
ml) at 0.degree. C. under an argon atmosphere was added
triethylsilane (0.48 ml, 3.0 mmol), followed by boron trifluoride
etherate (1.8 ml, 14.6 mmol). The reaction mixture was allowed to
warm to room temperature and stirred for 10 min, at which time was
added slowly 3M HCl. The mixture was extracted with EtOAc. The
organic extract was washed successively with H.sub.2O, aqueous
NaHCO.sub.3, H.sub.2O and saturated aqueous NaCl and dried. The
solvent was removed in vacuo, and the residue was purified by flash
chromatography on silica gel, eluting with 15% Et.sub.2O/hexanes to
provide the title compound as a mixture of .DELTA.1 and .DELTA.2
double bond isomers (820 mg, 67% for two steps).
[0127] g) Ethyl
(1RS,2SR,3SR)-1-(4-t-Butyldimethyl-siloxyphenyl)-3-(4-meth-
oxyphenyl)indane-2-carboxylate. To a solution of ethyl
(RS)-3-(4-t-butyldimethylsiloxyphenyl)-1-(4-methoxyphenyl)indane-2-carbox-
ylate (mixture of .DELTA.1 and .DELTA.2 double bond isomers) (750
mg, 1.5 mmol) in EtOH (25 ml) was added 5% palladium on activated
carbon (70 mg). The resulting suspension was stirred under an
atmosphere of H.sub.2 for 18 h, then was filtered through a pad of
Celite. The filtrate was concentrated under reduced pressure to
afford the title compound (730 mg, 97%), which was used without
further purification.
[0128] h) Ethyl
(1RS,2RS,3SR)-1-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)indan-
e-2-carboxylate. To a solution of ethyl
(1RS,2SR,3SR)-1-(4-t-butyldimethyl-
siloxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate (723 mg, 1.4
mmol) in EtOH (20 ml) was added 1M NaOH (1.6 ml, 1.6 mmol), and the
resulting mixture was stirred at room temperature for 30 min. The
mixture was then partitioned between 3M HCl and EtOAc. The aqueous
phase was extracted with EtOAc, and the combined organic extracts
were washed successively with H.sub.2O and saturated aqueous NaCl
and dried. The solvent was removed in vacuo to afford the title
compound (554 mg, 100%).
[0129] i) Ethyl (cis,
cis)-1.3-Di(4-methoxyphenyl)indane-2-carboxylate. To a solution of
ethyl (1RS,2RS,3SR)-1-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-
indane-2-carboxylate (270 mg, 0.7 mmol) in acetonitrile (5 ml) at
0.degree. C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 ml,
1.7 mmol), followed by methyl iodide (0.5 ml, 8.0 mmol). The
resulting mixture was allowed to warm to room temperature and was
stirred overnight. The mixture was partitioned between EtOAc and
dilute aqueous HCl. The organic extract was washed with saturated
aqueous NaCl and dried. The solvent was removed in vacuao, and the
residue was purified by flash chromatography to afford the title
compound (40 mg, 32% based on recovered starting material).
[0130] j) (trans, trans)-1,3-Di(4-methoxyphenyl)indane-2-carboxylic
acid. To a solution of ethyl (cis,
cis)-1,3-di(4-methoxyphenyl)indane-2-carboxy- late (35 mg, 0.09
mmol) in EtOH (3 ml) was added 1M NaOH (0.25 ml, 0.25 mmol), and
the resulting mixture was allowed to stir at room temperature
overnight. Thin layer chromatographic analysis at this time
indicated that the reaction was incomplete, so 5M NaOH (0.15 ml,
0.75 mmol) was added, and the mixture was allowed to stand at
0.degree. C. for 5 days. Water was added, and the mixture was
concentrated under reduced pressure. The aqueous residue was
extracted with Et.sub.2O (2x), and the Et.sub.2O extracts were
discarded. The aqueous phase was acidified with 6M HCl and
extracted several times with EtOAc. The combined EtOAc extracts
were washed successively with H.sub.2O and saturated aqueous NaCl
and dried. The solvent was removed in vacuo to provide an oily
residue which crystallized upon standing. The solid material was
recrystallized from EtOAc/hexanes to afford the title compound (19
mg, 59%); m.p. 192-193.degree. C. .sup.1H NMR (acetone-d.sub.6):
.delta.7.21-7.18 (m, 2H); 6.92 (dd, 4H, J=6.6 Hz, 2.1 Hz);
6.86-6.83 (m, 2H); 4.59 (d, 2H, J=10 Hz); 3.79 (s, 6H); 3.26 (t,
1H, J=10 Hz). MS: 392 [(M+NH.sub.4)+]. Anal. Calc. for
C.sub.24H.sub.22O.sub.4: C, 76.99; H, 5.92. Found C, 76.74; H
6.15.
EXAMPLE 3
(1RS
,2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-ca-
rboxylic acid
[0131] a) 2-(3,4-Methylenedioxybenzoyl)benzoic acid. To a solution
of 2-bromobenzoic acid (12 g, 0.06 mol) in THF (200 ml) at
-100.degree. C. under an argon atmosphere was added dropwise
n-butyl lithium (50 ml of 2.5M solution in hexanes, 0.125 mol),
maintaining the temperature below -90.degree. C. Upon completion of
the addition, the resulting solution was stirred at -100.degree. C.
for 1 h, at which time was added slowly a solution of piperonylic
acid chloride (11 g, 0.06 mol) in THF (50 ml), maintaining the
temperature below -90.degree. C. The resulting mixture was allowed
to warm to -80.degree. C. and stirred for 1 h, then was allowed to
slowly warm to room temperature and left to stand for 48 h. The
reaction mixture was concentrated under reduced pressure, and the
residue was partitioned between Et.sub.2O and 1M HCl. The organic
phase was extracted with 10% aqueous NaOH. The NaOH extract was
acidified with concentrated HCl, and the combined aqueous material
was extracted with Et.sub.2O. The Et.sub.2O extract was dried
(MgSO.sub.4) and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel, eluting with a
solvent gradient of 10-30% EtOAc/0.1% HOAc/hexanes to afford the
title compound as an off-white solid (4.5 g, 28%).
[0132] b) Diethyl 2-[2-(3,4-Methylenedioxybenzoyl)benzoyl-malonate.
A solution of 2-(3,4-methylenedioxybenzoyl)-benzoic acid (4.0 g,
14.8 mmol) in thionyl chloride (30 ml) was heated at reflux for 2
h, then allowed to cool and was concentrated under reduced
pressure. The residue was dissolved in Et.sub.2O (50 ml) and to
this was added a solution of diethyl magnesium malonate [prepared
by the method of Walker and Hauser, JACS, 68, 1386 (1946) using
magnesium (0.8 g, 33.3 mmol) and diethyl malonate (4.9 g, 30.6
mmol)] in Et.sub.2O. The resulting mixture was heated at reflux for
1 h, then allowed to cool and was poured into ice-cold 10% aqueous
H.sub.2SO.sub.4 (100 ml). The aqueous phase was extracted with
Et.sub.2O, and the combined organic material was washed with
saturated aqueous NaCl and dried. The solvent was removed under
reduced pressure to afford the title compound as an orange oil,
which was used without further purification.
[0133] c) Ethyl
3-(3,4-Methylenedioxyphenyl)-1-oxoindene-2-carboxylate. A solution
containing diethyl 2-[2-(3,4-methylenedioxybenzoyl)benzoylmalona-
te (crude material prepared above) in 5% aqueous Na.sub.2CO.sub.3
(100 ml) was heated at reflux for 10 min. The reaction mixture was
then allowed to cool, and the aqueous material was removed by
decantation. The residue was placed in H.sub.2O (50 ml), and the
mixture was heated at reflux, cooled and concentrat-ed under
reduced pressure. The residue was recrystallized from hexanes to
afford the title compound as a yellow solid (5.0 g, 100% for two
steps).
[0134] d) Ethyl
(1RS)-1-Hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyp-
henyl)indene-2-carboxylate. A solution of 4-bromoanisole (0.89 g,
5.0 mmol) in 9: 1 Et.sub.2O/ THF (10 ml) was added to magnesium
turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed
to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide
was added dropwise to a solution of ethyl
3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxy- late (0.77 g,
2.4 mmol) in 10 : 1 Et.sub.2O/ THF (55 ml) at 0.degree. C. The
resulting mixture was stirred at 0.degree. C. for 1 h and was then
partitioned between EtOAc and 1M HCl. The aqueous phase was
extracted with EtOAc, and the combined organic extracts were washed
successively with 5% aqueous NaHCO.sub.3 and saturated aqueous NaCl
and dried (MgSO.sub.4). The solvent was removed under reduced
pressure, and the residue was purified by flash chromatography on
silica gel, eluting with 10% EtOAc/ hexanes to afford the title
compound as a yellow glassy solid (0.80 g, 80%).
[0135] e) Ethyl
(RS)-1-(4-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)inde-
ne-2-carboxylate. To a solution of ethyl
(1RS)-1-hydroxy-1-(4-methoxypheny-
l)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9
mmol) in CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C. under an argon
atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by
boron trifluoride etherate (1 ml, 8.1 mmol). The resulting solution
was stirred at 0.degree. C. for 10 min, and was then partitioned
between EtOAc and 3M HCl. The organic extract was washed with
saturated aqueous NaCl and dried (MgSO.sub.4). The solvent was
removed in vacua, and the residue was filtered through a pad of
silica gel, eluting with CH.sub.2CH.sub.2. The title compound
(mixture of .DELTA.1 and .DELTA.2 double bond isomers) was obtained
as a glassy, yellow solid (0.72 g, 94%).
[0136] f) Ethyl
(1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphe-
nyl)indane-2-carboxylate. To a solution of ethyl
(RS)-1-(4-methoxyphenyl)--
3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.72 g, 1.7
mmol) in EtOH (30 ml) was added 10% palladium on activated carbon
(1 g). The resulting suspension was stirred under an atmosphere of
H.sub.2 for 56 h and filtered. The filtrate was concentrated under
reduced pressure to afford the title compound as a yellow solid
(0.70 g, 95%), which was used without further purification.
[0137] g)
(1RS,2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)in-
dane-2-carboxylic acid. To a solution of ethyl
(1RS,2RS,3SR)-1-(4-methoxyp-
henyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (0.10 g,
0.2 mmol) in EtOH (5 ml) was added a solution of sodium hydroxide
(0.10 g, 2.5 mmol) in H.sub.2O (2 ml). The resulting mixture was
stirred at room temperature overnight. The mixture was acidified,
and the solid which formed was collected by filtration and dried
under reduced pressure to afford the title compound as a tan solid
(0.04 g, 86%). .sup.1H NMR (CDCl.sub.3): .delta.7.25 (m, 5H); 6.90
(m, 4H); 6.77 (d, 2H, J=7 Hz); 5.95 (m, 2H); 4.61 (d, 2H, J=10 Hz);
3.81 (s, 3H); 3.25 (t, 2H, J=10 Hz). MS: 387 [(M-H+]. Anal. Calc.
for C.sub.24H.sub.20O.sub.5.multidot.1/8 H.sub.2O: C, 73.79; H,
5.22. Found C, 76.73; H 5.21.
EXAMPLE 4
(1RS, 2SR,
3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-ca-
rboxylic acid
[0138] a) Ethyl
(1RS)-1-(4-Fluorophenyl)-1-hydroxy-3-(3,4-methylenedioxyph-
enyl)indene-2-carboxylate. To a solution of ethyl
3-(3,4-methylenedioxyphe- nyl)-1-oxoindene-2-carboxylate (100 mg,
0.31 mmol) in THF (5 ml) under an argon atmosphere at 0.degree. C.
was added a solution of freshly prepared 4-fluorophenyl magnesium
bromide (0.62 mmol). After stirring for 45 min, the mixture was
partitioned between 3M HCl and EtOAc. The organic extract was
washed successively with H.sub.2O, 5% aqueous NaHCO.sub.3 and
saturated aqueous NaCl. The solvent was removed in vacuo, and the
residue was purified by flash chromatography, eluting with 15%
EtOAc/ hexanes to afford the title compound (45 mg, 35%).
[0139] b) Ethyl
(RS)-1-(4-Fluorophenyl)-3-(3,4-methylene-dioxyphenyl)inden-
e-2-carboxylate. To a solution of ethyl
(1RS)-1-(4-fluorophenyl)-hydroxy-3-
-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol)
in CH.sub.2Cl.sub.2 (3 ml) at 0.degree. C. was added triethylsilane
(38 .mu.l, 0.24 mmol), followed by boron trifluoride etherate (121
.mu.l, 0.98 mmol). The reaction mixture was allowed to warm to room
temperature and stirred for 15 min, at which time was added slowly
3M HCl. The mixture was extracted with EtOAc. The organic extract
was washed successively with H.sub.2O, 5% aqueous NaHCO.sub.3 and
saturated aqueous NaCl. The solvent was removed in vacuo to provide
the title compound (40 mg, 90%) as a mixture of .DELTA.1 and
.DELTA.2 double bond isomers.
[0140] c) Ethyl (1RS, 2RS,
3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyph-
enyl)indane-2-carboxylate. To a solution of ethyl
(RS)-1-(4-fluorophenyl)--
3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (40 mg, 0.10 mmol)
in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg).
The resulting suspension was stirred under an atmosphere of H.sub.2
overnight, then was filtered through a pad of Celite. The filtrate
was concentrated under reduced pressure to afford the title
compound (40 mg, 100%), which was used without further
purification.
[0141] d) (1RS, 2SR,
3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)i-
ndane-2-carboxylic acid. To a solution of ethyl
(1RS,2RS,3SR)-1-(4-fluorop-
henyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (60 mg,
0.15 mmol) in EtOH (0.5 ml) was added 6M KOH (0.14 ml, 0.84 mmol).
The resulting mixture was allowed to stir at room temperature
overnight, then was concentrated under reduced pressure. The
residue was partitioned between H.sub.2O and Et.sub.2O. The aqueous
phase was acidified with 3M HCl and extracted several times with
EtOAc. The combined EtOAc extracts were washed successively with
H.sub.2O and saturated aqueous NaCl and dried (MgSO.sub.4). The
solvent was removed in vacuo to afford an oil, which was
crystallized from EtOAc/ hexanes. The title compound was obtained
as an off-white crystalline solid (22 mg, 39%); m.p.
146-149.degree. C. .sup.1H NMR (CDCl.sub.3): .delta.7.23 (m, 4H);
6.96 (m, 1H); 6.90 (m, 1H); 6.79 (s, 2H); 6.75 (s, 1H); 5.96 (m,
2H); 4.62 (apparent br t, 2H, J=10 Hz); 3.25 (t, 1H, J =10 Hz). MS
m/e (rel. int.): 753 [(2M+1)+, 3]. Anal. Calcd. for
C.sub.23H.sub.17FO.sub.4: C, 73.40; H, 4.55. Found: C, 73.19; H,
4.45.
EXAMPLE 5
(1RS, 2SR,
3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-c-
arboxylic acid
[0142] a) Ethyl
(1RS)-1-Hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyp-
henyl)indene-2-carboxylate. To a solution of ethyl
3-(3,4-methylenedioxyph- enyl)-1-oxoindene-2-carboxylate (100 mg,
0.31 mmol) in THF (2 ml) under an argon atmosphere at 0.degree. C.
was added a solution of freshly prepared 3-methoxyphenyl magnesium
bromide (0.31 mmol). After stirring for 15 min, additional
3-methoxyphenyl magnesium bromide (0.06 mmol) was added. Stirring
was continued for 45 min, at which time thin layer chromatographic
analysis indicated that the reaction was incomplete. Additional
3-methoxyphenyl magnesium bromide (0.12 mmol) was added. After
stirring for 2 h more, the mixture was partitioned between 3M HCl
and EtOAc. The organic extract was washed successively with
H.sub.2O, 5% aqueous NaHCO.sub.3, H.sub.2O and saturated aqueous
NaCl. The solvent was removed in vacuo, and the residue was
purified by flash chromatography, eluting with 15% EtOAc/ hexanes
to afford the tide compound (150 mg, 100%).
[0143] b) Ethyl (1RS
)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)ind-
ene-2-carboxylate. To a solution of ethyl
(1RS)-1-hydroxy-1-(3-methoxyphen-
yl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35
mmol) in CH.sub.2Cl.sub.2 was added triethylsilane (67 .mu.l, 0.42
mmol), followed by boron trifluoride etherate (213 .mu.l, 1.73
mmol). The reaction mixture was allowed to stir for 30 min, at
which time was added slowly 5% aqueous HCl. The mixture was
extracted with EtOAc. The organic extract was washed successively
with H.sub.2O, 5% aqueous NaHCO.sub.3, H.sub.2O and saturated
aqueous NaCl and dried (MgSO.sub.4). The solvent was removed in
vacuo, and the residue was purified by flash chromatography,
eluting with 10% EtOAc/ hexanes to provide the title compound (45
mg, 31%) as a mixture of .DELTA.1 and .DELTA.2 double bond
isomers.
[0144] c) Ethyl (1RS, 2RS,
3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyp-
henyl)indane-2-carboxylate. To a solution of ethyl
(RS)-1-(3-methoxyphenyl-
)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11
mmol) in EtOH (3 ml) was added 10% palladium on activated carbon
(45 mg). The resulting suspension was shaken on a Parr hydrogenator
at 50 psi H.sub.2 overnight, then was filtered through a pad of
Celite. The filtrate was concentrated under reduced pressure to
afford the title compound (43 mg, 94%), which was used without
further purification.
[0145] d)
(1RS,2SR,3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)in-
dane-2-carboxylic acid. To a solution of ethyl (1RS, 2RS, 3SR)
-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate
(43 mg, 0.10 mmol) in EtOH (1 ml) was added 6M KOH (0.10 ml, 0.60
mmol). The resulting mixture was allowed to stir at room
temperature overnight, then was partitioned between H.sub.2O and
Et.sub.2O. The aqueous phase was acidified with 3M HCl and
extracted several times with EtOAc. The combined EtOAc extracts
were washed successively with H.sub.2O and saturated aqueous NaCl
and dried (MgSO.sub.4). The solvent was removed in vacuo to afford
an oil, which was crystallized from Et.sub.2O/ hexanes. The title
compound was obtained as a solid; m.p. 131-133.degree. C. .sup.1H
NMR (CDCl.sub.3): .delta.7.21 (m, 3H); 6.97-6.73 (m, 8H); 5.95 (m,
2H); 4.61 (apparent br t, 2H, J=9 Hz); 3.67 (s, 3H); 3.30 (t, 1H,
J=9 Hz). MS m/e (rel. int.) : 777 [(2M+1).sup.+, 65]. Anal. Calcd.
for C.sub.24H.sub.20O.sub.5: C, 74.21; H, 5.19. Found: C, 74.71; H,
5.47.
EXAMPLE 6
(1RS, 3RS)-1,3-Di-(3,4-methylenedioxyphenyl)-indane-2-carboxylic
acid
[0146] a) Ethyl
(1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2--
carboxylate. To dry magnesium turnings (0.25 g, 10 mmol) under an
argon atmosphere was added a solution of
4-bromo-1,2-methylenedioxybenzene (2.1 g, 10 mmol) in 1: 10 THF/
Et.sub.2O (22 ml). The resulting solution was allowed to stir at
room temperature for 2 h. During this time, additional THF (4 ml)
was added. The resulting 3,4-methylenedioxyphenylmagnesium bromide
was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-o-
xoindene-2-carboxylate (0.50 g, 2 mmol) in 1: 4 THF/ Et.sub.2O (25
ml) under an argon atmosphere at 0.degree. C. The resulting mixture
was stirred at 0.degree. C. for 15 min, at which time 1M HCl (50
ml) was added. The phases were separated and the aqueous phase was
extracted with Et.sub.2O. The combined organic extracts were washed
with saturated aqueous NaCl and dried (MgSO.sub.4). The solvent was
removed in vacua, and the residue was purified by flash
chromatography, eluting with 10% EtOAc/ hexanes to afford the title
compound as a yellow solid (0.29 g, 42%).
[0147] b) Ethyl
(RS)-1,3-Di-(3,4-methylenedioxyphenyl)indene-2-carboxylate- . To a
solution of ethyl
(1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxy-
indene-2-carboxylate (0.29 g, 0.65 mmol) in CH.sub.2Cl.sub.2 (3 ml)
at 0.degree. C. under an argon atmosphere was added triethylsilane
(91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml,
2.4 mmol). The reaction mixture was stirred for 10 min, at which
time was added ice-cold 1M HCl, and the mixture was extracted with
EtOAc. The organic extract was washed with saturated aqueous NaCl
and dried (MgSO.sub.4). The solvent was removed in vacuo, and the
residue was placed on a small pad of silica gel, eluting with
CH.sub.2Cl.sub.2 to provide the title compound (257 mg, 92%).
[0148] c) Ethyl (1RS,
3RS)-1,3-Di-(3,4-methylenedioxy-phenyl)indane-2-carb- oxylate.
Ethyl (RS)-1,3-di-(3,4-Methylenedioxyphenyl)indene-2-carboxylate
(163 mg, 0.38 mmol) was placed in MeOH (0.05 ml), and to this was
added SmI.sub.2 (10 ml of 0.M solution in THF, 1.0 mmol). The
resulting mixture was stirred under an argon atmosphere overnight,
at which time thin layer chromatographic analysis indicated that
the reaction was incomplete. Additional SmI.sub.2 (5 ml of 0.1M
solution in THF, 0.5 mmol) was added, and stirring was continued
for 2 h. The reaction mixture was partitioned between Et.sub.2O and
5% aqueous Na.sub.2S.sub.2O.sub.3. The organic extract was washed
with saturated aqueous NaCl and dried (MgSO.sub.4). The solvent was
removed under reduced pressure, and the residue was purified by
flash chromatography, eluting with 10% EtOAc/ hexanes to afford the
title compound as a colorless, glassy solid (120 mg, 75%).
[0149] d) (1RS,
3RS)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxylic acid. To
a solution of ethyl (1RS, 3RS)-1,3-di-(3,4-methylenedioxyphenyl)-
indane-2-carboxylate (75 mg, 0.17 mmol) in EtOH (20 ml) was added
NaOH (0.10 g, 2.5 mmol). The resulting mixture was allowed to stir
at room temperature for 3 d, at which time thin layer
chromatographic analysis indicated that the reaction was
incomplete. The mixture was then heated at reflux for 36 h, allowed
to cool and was concentrated under reduced pressure. To the residue
was added concentrated HCl, and the solid which formed was
collected by filtration and dried. The solid was triturated with
boiling hexanes to afford the title compound as a white solid (50
mg, 73%); m.p. 182-185.degree. C. .sup.1H NMR (CDCl.sub.3) :
.delta.7.25 (m, 2H); 7.15 (m, 1H); 7.00 (m, 1H); 6.76 (s, 2H); 6.68
(m, 2H); 6.50 (dd, 1H, J=8, 1 Hz); 6.40 (d, 1H, J=2 Hz); 5.94 (s,
2H); 5.90 (d, 1H, J=1 Hz); 5.87 (d, 1H, J=1 Hz); 4.84 (d, 1H, J=10
Hz); 4.78 (d, 1H, J=10 Hz); 3.63 (dd, 1H, J=10 Hz, 9 Hz). MS: 402
(M).sup.+. Anal. Calcd. for C.sub.24H.sub.18O.sub.6.multidot.1/5
H.sub.2O: C, 71.00; H, 4.52. Found: C, 71.13; H, 4.46.
EXAMPLE 7
(trans, trans)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxylic
acid
[0150] a) Ethyl (cis,
cis)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carbo- xylate. To a
solution of ethyl (RS)-1,3-di-(3,4-methylenedioxyphenyl)inden-
e-2-carboxylate (93 mg, 0.22 mmol) in EtOH (2 ml) was added 10%
palladium on activated carbon (0.10 g). The resulting suspension
was shaken on a Parr hydrogenator at 55 psi H.sub.2 for 2 d, then
was filtered through a pad of Celite. The filtrate was concentrated
under reduced pressure to afford the title compound (45 mg, 48%) as
a glassy, yellow solid, which was used without further
purification.
[0151] b) (trans,
trans)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxy- lic acid.
To a solution of ethyl (cis, cis)-1,3-di-(3,4-methylenedioxyphen-
yl)indane-2-carboxylate (45 mg, 0.1 mmol) in 2: 1 EtOH/ H.sub.2O
(15 ml) was added sodium hydroxide (50 mg, 1.2 mmol). The resulting
solution was allowed to stir at room temperature overnight, then
was concentrated under reduced pressure. The residue was treated
with concentrated HCl, and the solid which formed was collected by
filtration and dried. The solid was recrystallized from Et.sub.2O/
hexanes to afford the title compound as a light tan solid (12 mg,
30%); m.p. 188-191.degree. C.
EXAMPLE 8
(1RS, 2RS,
3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-carboxylic
acid
[0152] a) Ethyl
(1RS)-1-Hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylinden-
e-2-carboxylate. To a solution of ethyl
1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml)
under an argon atmosphere at 0.degree. C. was added a solution of
freshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4
mmol). After stirring for 30 min, the mixture was partitioned
between 3M HCl and EtOAc. The organic extract was washed
successively with H.sub.2O, 5% aqueous NaHCO.sub.3 and saturated
aqueous NaCl and dried (MgSO.sub.4). The solvent was removed in
vacuo, and the residue was purified by flash chromatography,
eluting with 10% EtOAc/ hexanes to afford the title compound (1.03
g, 72%).
[0153] b) Ethyl
(RS)-1-(3,4-Methylenedioxyphenyl)-3-phenylindene-2-carboxy- late.
To a solution of ethyl
(1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)--
3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in
CH.sub.2Cl.sub.2 (40 mL) was added triethylsilane (0.49 ml, 3.07
mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol).
The reaction mixture was allowed to stir for 15 min, at which time
was added slowly 3M HCl. The mixture was extracted with EtOAc. The
organic extract was washed successively with H.sub.2O, 5% aqueous
NaHCO.sub.3 and saturated aqueous NaCl. The solvent was removed in
vacuo to provide the title compound (1.00 g, 100%) as a mixture of
.DELTA.1 and .DELTA.2 double bond isomers.
[0154] c) Ethyl (1RS, 2SR,
3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindan- e-2-carboxylate.
To a solution of ethyl (RS)-1-(3,4-methylenedioxyphenyl)--
3-phenylindene-2-carboxylate (1.00 g, 2.60 mmol) in EtOH (25 ml)
was added 10% palladium on activated carbon (30 mg). The resulting
suspension was stirred under an atmosphere of H.sub.2 overnight.
Thin layer chromatographic analysis indicated that the reaction was
incomplete, so additional 10% palladium on activated carbon (30 mg)
was added, and the mixture was shaken on a Parr hydrogenator at 30
psi H.sub.2 for 2 d. At this time, thin layer chromatographic
analysis again indicated that the reaction was incomplete. The
reaction mixture was filtered through a pad of Celite, and 10%
palladium on activated carbon (250 mg) was added. The reaction
mixture was shaken on a Parr hydrogenator at 60 psi H.sub.2
overnight. Filtration and repetition of the latter hydrogenation
conditions led to complete consumption of starting material. The
reaction mixture was filtered through a pad of Celite, and the
filtrate was concentrated under reduced pressure to afford the
title compound (650 mg, 65%), which was used without further
purification.
[0155] d) (1RS, 2RS,
3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-ca- rboxylic
acid. To a solution of ethyl (1RS, 2SR, 3SR)-1-(3,4-methylenediox-
yphenyl)-3-phenylindane-2-carboxylate (650 mg, 1.68 mmol) in EtOH
containing a few drops of THF was added 6M KOH (1.68 ml, 10.1
mmol). The resulting mixture was allowed to stir at room
temperature overnight, then was concentrated under reduced
pressure. The residue was partitioned between H.sub.2O and
Et.sub.2O. The aqueous phase was acidified with 3M HCl and
extracted several times with EtOAc. The combined EtOAc extracts
were washed successively with H.sub.2O and saturated aqueous NaCl
and dried (MgSO.sub.4). The solvent was removed in vacuo to afford
an oil, which was crystallized from EtOAc/ hexanes. The title
compound was obtained as a solid (305 mg, 51%); m.p.
186-187.degree. C. Anal. Calcd. for C.sub.23H.sub.18O.sub.4: C,
77.08; H, 5.06. Found: C, 76.60; H, 5.08.
EXAMPLE 9
(1RS, 2SR,
3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-(tetraz-
ol-5-yl)indane
[0156] a) (1RS, 2SR,
3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-
indane-2-carboxamide. A mixture of (1RS, 2SR,
3SR)-1-(4-methoxyphenyl)-3-(-
3,4-methylenedioxyphenyl)indane-2-carboxylic acid (250 mg, 0.64
mmol) in SOCl.sub.2 (2.5 ml) was allowed to stir overnight under an
argon atmosphere. The reaction mixture was concentrated under
reduced pressure, and the residue was dissolved in benzene (5 ml).
To the resulting mixture under an argon atmosphere was added
concentrated NH.sub.4OH (5 ml). The solid which formed was
collected by filtration, washed with H.sub.2O and dried in vacuo to
afford the title compound (185 mg, 75%).
[0157] b) (1RS, 2SR,
3SR)-1-(4-Methoxyphenyl)-3-(3,4-methyl-enedioxyphenyl-
)indane-2-carbonitrile. To ice-cold DMF (1 ml) under an argon
atmosphere was added oxalyl chloride (68ml, 0.78mmol). After
stirring for 5 min at 0.degree. C., a solution of (1RS, 2SR,
3SR)-1-(4-methoxyphenyl)-3-(3,4-me-
thylenedioxyphenyl)indane-2-carboxamide (150 mg, 0.39 mmol) in DMF
(2 ml) was added, and stirring was continued for an additional 10
min at 0.degree. C. The reaction mixture was partitioned between
EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and
the combined organic extracts were washed successively with
H.sub.2O, aqueous NaHCO.sub.3, H.sub.2O and saturated aqueous NaCl
and dried. The solvent was removed in vacuo to afford the title
compound as a white solid (135 mg, 94%) which was used without
further purification.
[0158] c) (1RS, 2SR,
3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-
-2-(tetrazol-5-yl)indane. To THF (2.5 ml) at -78.degree. C. under
an argon atmosphere was added aluminum chloride (90 mg, 0.67 mmol).
After slowly warming to room temperature, sodium azide (130 mg, 2.2
mmol) was added, and the resulting mixture was heated at 70.degree.
C. for 5 min, then cooled to room temperature. To the reaction
mixture was added a solution of (1RS, 2SR,
3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-
-2-carbonitrile (125 mg, 0.34 mmol) in THF (2.5 ml). After heating
at 70.degree. C. overnight, thin layer chromatographic analysis of
the reaction mixture indicated the presence of starting material,
so additional Al(N.sub.3).sub.3 was prepared as above (1.34 mmol)
in THF. To this was added the reaction mixture, and heating at
70.degree. C. was resumed for an additional 5 h. The mixture was
partitioned between EtOAc and 3M HCl. The aqueous phase was
extracted with EtOAc, and the combined organic extracts were washed
successively with H.sub.2O and saturated aqueous NaCl and dried.
The solvent was removed in vacua, and the residue was crystallized
from EtOAc/ hexanes to afford the title compound (78 mg, 56%). A
portion of this material was further purified by MPLC (LiChroprep
RP-18, MeOH/H.sub.2O=60/40) and then recrystallized; m.p.
155-157.degree. C. (EtOAc/ hexanes). .sup.1H NMR (CDCl.sub.3):
.delta.7.28-7.15 (m, 4H); 7.03 - 6.95 (m, 2H); 6.87-6.84 (m, 2H);
6.74 (s, 3H); 5.94 (d, 1H, J=1.2 Hz); 5.92 (d, 1H, J=1.2 Hz); 4.79
(d, 1H, J=11.6 Hz); 4.73 (d, 1H, J=11.6 Hz); 3.79 (S, 3H); 3.65 (t,
1H, J=11.6 Hz). MS (m/e) : 413.2 [(M+H).sup.+].
EXAMPLE 10
(1RS, 2SR,
3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-c-
arboxylic acid
[0159] a) Ethyl
(1RS)-1-Hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyp-
henyl)indene-2-carboxylate. To dry magnesium turnings (81 mg, 3,4
mmol) under an argon atmosphere was added a solution of
2-bromoanisole (0.64 g, 3,4 mmol) in 5 :1 THF/ Et.sub.2O (3 ml). A
portion of the resulting 2-methoxyphenyl magnesium bromide solution
(0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl
3-(3,4-methylenedioxyphenyl)-1-oxoindene-- 2-carboxylate (100 mg,
0.34 mmol) in THF (6 ml) under an argon atmosphere at 0.degree. C.
After stirring for 15 min, the mixture was partitioned between 3M
HCl and EtOAc. The organic extract was washed successively with
H.sub.2O, 5% aqueous NaHCO.sub.3, H.sub.2O and saturated aqueous
NaCl. The solvent was removed in vacuo, and the residue was
purified by flash chromatography, eluting with 15% EtOAc/ hexanes
to afford the title compound. (100 mg, 68%).
[0160] b) Ethyl
(RS)-1-(2-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)inde-
ne-2-carboxylate. To a solution of ethyl
(1RS)-1-hydroxy-1-(2-methoxypheny-
l)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23
mmol) in CH.sub.2Cl.sub.2 (5 ml) was added triethylsilane (32 mg,
0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05
mmol). The reaction mixture was allowed to warm to room temperature
and stirred for 10 min, at which time was added slowly 3M HCl. The
mixture was extracted with EtOAc. The organic extract was washed
successively with H.sub.2O, 5% aqueous NaHCO.sub.3, H.sub.2O and
saturated aqueous NaCl and dried (MgSO.sub.4). The solvent was
removed in vacuo to provide the title compound (91 mg, 96%) as a
mixture of .DELTA.1 and .DELTA.2 double bond isomers.
[0161] c) Ethyl (1RS, 2RS,
3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyp-
henyl)indane-2-carboxylate. To a solution of ethyl
(RS)-1-(2-methoxyphenyl-
)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (90 mg, 0.22
mmol) in EtOH (10 ml) was added 10% palladium on activated carbon
(90 mg). The resulting suspension was shaken on a Parr hydrogenator
at 60 psi H.sub.2 overnight, then was filtered through a pad of
Celite. The filtrate was concentrated under reduced pressure to
afford the title compound (90 mg, 100%), which was used without
further purification.
[0162] d) (1RS, 2SR,
3RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-
indane-2-carboxylic acid. To a solution of ethyl (1RS, 2RS,
3RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate
(90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF was
added 6M KOH (0.22 ml, 1.32 mmol). The resulting mixture was
allowed to stir at room temperature overnight, then was
concentrated under reduced pressure. The residue was partitioned
between H.sub.2O and Et.sub.2O. The aqueous phase was acidified
with 3M HCl and extracted with EtOAc. The EtOAc extract was washed
successively with H.sub.2O and saturated aqueous NaCl and dried
(MgSO.sub.4). The solvent was removed in vacuo to afford the title
compound (40 mg, 49%). .sup.1H NMR (CDCl.sub.3): .delta.7.37-6.73
(m, 1H); 5.93 (m, 2H); 5.03 (d, 1H, J=10 Hz); 4.67 (d, 1H, J=10
Hz); 3.70 (s, 3H); 3.38 (t, 1H, J=10 Hz).
EXAMPLE 11
(1RS, 2SR,
3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-
indane-2-carboxylic acid, sodium salt
[0163] a) 3-Benzyloxyacetophenone. To a mixture of sodium hydride
(4.5 g of 80% mineral oil dispersion, 0.15 mol), which had been
washed free of mineral oil, in DMF (25 ml) was added, dropwise with
cooling, a solution of 3-hydroxyacetophenone (20.5 g, 0.15 mol) in
DMF (25 ml). Upon completion of the addition, the mixture was
allowed to stir at room temperature for 15 min, at which time was
added benzyl bromide (25.6 g, 0.15 mol). The resulting mixture was
allowed to stir at room temperature overnight, then was partitioned
between EtOAc and 3M HCl. The aqueous phase was extracted with
EtOAc, and the combined organic extracts were washed successively
with 1M NaOH, H.sub.2O and saturated aqueous NaCl and dried. The
solvent was removed in vacuo to afford the title compound (33 g,
97%), which was used without further purification.
[0164] b) Methyl 2-(3-Benzyloxy)benzoylacetate. To a mixture of
sodium hydride (28.3 g of 80% mineral oil dispersion, 0.94 mol),
which had been washed free of mineral oil, in dimethyl carbonate
(100 ml) under an argon atmosphere was added, over 30 min, a
solution of 3-benzyloxyacetophenone (92.3 g, 0.41 mol) in dimethyl
carbonate (150 ml). Upon completion of the addition, the mixture
was heated at reflux for 30 min, then was cooled in an ice bath and
quenched by the slow addition of 3M HCl. The mixture was
partitioned between EtOAc and 3M HCl, and the aqueous phase was
extracted with EtOAc. The combined organic extracts were washed
successively with H.sub.2O, aqueous NaHCO.sub.3, H.sub.2O and
saturated aqueous NaCl and dried. The solvent was removed in vacuo
to afford the title compound (112.5 g, 97%).
[0165] c) Methyl
2-(3-Benzyloxybenzoyl)-3-(3,4-methylenedioxy-phenyl)prope- noate. A
mixture containing methyl 2-(3-benzyloxy)benzoylacetate (75.0 g,
0.26 mol), piperonal (43.6 g, 0.29 mol), acetic acid (3.6 ml) and
piperidine (1.2 ml) in benzene (70 ml) was heated at reflux, with
azeotropic removal of H.sub.2O. After heating at reflux for 4 h,
the reaction mixture was concentrated in vacua, and the residue was
crystallized from EtOH to afford the title compound (93.5 g, 85%);
m.p. 116-118.degree. C.
[0166] d) Methyl (1RS,
2SR)-5-Benzyloxy-1-(3,4-methylenedioxy-phenyl)-3-ox-
oindane-2-carboxylate. To trifluoroacetic acid (150 ml) at
0.degree. C. under an argon atmosphere was added methyl
2-(3-benzyloxybenzoyl)-3-(3,4-- methylene-dioxyphenyl)propenoate
(80.0 g, 0.19 mol). The mixture was allowed to warm to room
temperature and stirred for 30 min, at which time the mixture was
concentrated under reduced pressure. The residue was dissolved in
EtOAc and washed successively with aqueous NaHCO.sub.3, H.sub.2O
and saturated aqueous NaCl and dried. The solvent was removed in
vacuo, and the oily residue was crystallized from EtOAc/ hexanes to
afford the title compound (51.3 g, 64%); m.p. 148-150.degree.
C.
[0167] e) Methyl
5-Benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxoindene-2-ca-
rboxylate. To a solution of methyl
5-benzyloxy-1-(3,4-methylenedioxyphenyl-
)-3-oxoindane-2-carboxylate (27.3 g, 65.6 mmol) in benzene (90 ml),
cooled in an ice-H.sub.2O bath, was added
2,3-dichloro-5,6-dicyano-1,4-benzoquin- one (15.4 g, 67.8 mmol).
The resulting mixture was stirred at 0.degree. C. for 1 h, allowed
to warm to room temperature for 1.5 h, and finally warmed to
40.degree. C. for 1 h. The solid which formed was removed by
filtration and washed with benzene. The combined filtrate and
washings were poured into EtOAc (200 ml) and washed successively
with aqueous Na.sub.2CO.sub.3 (3x), H.sub.2O (3x), 3M HCl, H.sub.2O
(3x) and saturated aqueous NaCl and dried. The solvent was removed
in vacua, and the residue was crystallized from EtOAc/ hexanes to
afford the title compound (16.4 g, 60%) as a red crystalline solid;
m.p. 140-141.degree. C.
[0168] f) Methyl
(3RS)-5-Benzyloxy-3-hydroxy-3-(4-methoxy-phenyl)-1-(3,4-m-
ethylenedioxyphenyl)indene-2-carboxylate. To dry magnesium turnings
(0.96 g, 40 mmol) under an argon atmosphere was added a solution of
4-bromoanisole (7.48 g, 40 mmol) in 9: 1 Et.sub.2O/THF (50 ml). The
resulting 4-methoxyphenyl magnesium bromide solution was added
portionwise to a solution of methyl
5-benzyloxy-1-(3,4-methylenedioxyphen-
yl)-3-oxoindene-2-carboxylate (8.29 g, 20 mmol) in THF (250 ml)
under an argon atmosphere. Upon completion of the addition, the
mixture was quenched by the addition of 3M HCl and extracted with
EtOAc. The organic extract was washed successively with H.sub.2O,
aqueous NaHCO.sub.3, H.sub.2O and saturated aqueous NaCl. The
solvent was removed in vacuo to afford the title compound (11.58 g,
100%), which was used without further purification.
[0169] g) Methyl
(RS)-5-Benzyloxy-3-(4-methoxyphenyl)-1-(3,4-methylenediox-
yphenyl)indene-2-carboxylate. To a solution of methyl
(3RS)-5-benzyloxy-3-hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphen-
yl)indene 2-carboxylate (crude material prepared above) in
CH.sub.2Cl.sub.2 (75 ml) under an argon atmosphere at 0.degree. C.
was added triethylsilane (3.9 ml, 23.6 mmol), followed by boron
trifluoride etherate (14.7 ml, 120 mmol). The reaction mixture was
stirred for 10 min at 0.degree. C., at which time the mixture was
partitioned between 3M HCl and EtOAc. The organic extract was
washed successively with H.sub.2O, aqueous NaHCO.sub.3, H.sub.2O
and saturated aqueous NaCl and dried. The solvent was removed in
vacuo, and the residue was purified by flash chromatography,
eluting with a solvent gradient of 25-45% Et.sub.2O/ hexanes. The
title compound (8.41 g, 83% for two steps) was isolated as a
mixture of .DELTA.1 and .DELTA.2 double bond isomers.
[0170] h) Methyl (1RS, 2RS,
3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl)indane-2-carboxylate. To a degassed solution of
methyl
(RS)-5-benzyloxy-3-(4-methoxyphenyl)-2-(3,4-methylene-dioxyphenyl)indene--
2-carboxylate (6.60 g, 13.0 mmol) in EtOAc (25 ml) and EtOH (175
ml) was added 5% palladium on activated carbon (0.6 g). The
resulting suspension was shaken on a Parr hydrogenator at 60 psi
H.sub.2 for 20 h, at which time NMR analysis of the reaction
mixture indicated that the reaction was incomplete. The catalyst
was removed by filtration through a pad of Celite, and fresh 5%
palladium on activated carbon (0.6 g) was added. The mixture was
shaken on a Parr hydrogenator at 60 psi H.sub.2 for an additional
48 h. The catalyst was removed by filtration through a pad of
Celite, and the filtrate was concentrated under reduced pressure.
The residue was crystallized from EtOAc/ hexanes to afford the
title compound (4.83 g, 89%); m.p. 187-188.degree. C.
[0171] i) (1RS, 2SR,
3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedi-
oxyphenyl)indane-2-carboxylic acid, sodium salt. To a solution of
methyl (1 RS, 2RS, 3S
R)-5-hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxy-phe-
nyl)indane-2-carboxylate (150 mg, 0.36 mmol) in EtOH (4 ml) was
added 10% NaOH (4 ml), and the resulting mixture was allowed to
stir under an argon atmosphere overnight. Water (5 ml) was added,
and the mixture was concentrated under reduced pressure. The
concentrate was extracted with Et.sub.2O, and the aqueous phase was
acidified and extracted with EtOAc. The EtOAc extract was washed
successively with H.sub.2O and saturated aqueous NaCl and dried.
The solvent was removed in vacuo. The sodium salt was prepared, and
a portion of this (100 mg) was purified by reverse-phase
chromatography to afford the title compound (73 mg, 48%).
Trituration of this material with EtOAc provided a white
crystalline solid; m.p. 198.degree. C. (dec). .sup.1H NMR
(MeOH-d.sub.4): .delta.7.20 (dd, 2H, J=6.8 Hz, 2.0 Hz); 6.85 (dd,
2H, J=6.8 Hz, 2.0 Hz); 6.80-6.64 (m, 5H); 6.25 (s, 1H); 5.88-5.87
(m, 2H); 4.47 (d, 1H, J=10 Hz); 4.43 (d, 1H, J=10 Hz); 3.76 (s,
3H); 3.03 (t, 1H, J=10 Hz). MS (m/e): 427 [(M+H).sup.+].
EXAMPLE 12
+(1S, 2R,
3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyph-
enyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid
[0172] a) 3-(Prop-1-yloxy)acetophenone. To a slurry of NaH (13.84
g, 0.58 mol) in dry DMF (50 mL) at 0.degree. C., was added a
solution of 3-hydroxyacetophenone (50 g, 0.37 mol). After stirring
for 30 min. 1-iodopropane (70 mL, 0.72 mol) was added and the
mixture stirred overnight at room temperature. The mixture was
diluted with dry DMF (50 mL) and further NaH (2.77 g, 0.12 mol)
added followed by 1-iodopropane (23 mL, 0.24 mol). After 1 h. TLC
indicated that the reaction was complete and the product was
cautiously quenched with 6M HCl and extracted with EtOAc. The EtOAc
extract was washed successively with H.sub.2O, 10% aqueous NaOH and
then brine. After drying (MgSO.sub.4), filtration and evaporation
gave the title compound (65 g, 98%) as a light yellow oil which was
used without further purification. Anal. Calc. for
C.sub.11H.sub.14O.sub.2: C, 74.13; H, 7.89. Found: C, 73.85; H,
7.86.
[0173] b) Methyl 3-(Prop-1-yloxy)benzoylacetate. To a suspension of
NaH (12 g, 0.5 mol) in dry dimethyl carbonate (50 mL) was added
slowly a solution of 3-(Prop-1-yloxy)acetophenone (65 g, 0.37 mol)
in dry dimethyl carbonate (100 mL). During the addition the
exothermicity of the reaction caused refluxing. Following the
addition the mixture was stirred mechanically overnight and was
then quenched cautiously with 3M HCl and extracted with EtOAc. The
EtOAc extract was washed successively with H.sub.2O, 5% aqueous
NaHCO.sub.3, H.sub.2O and brine. After drying (MgSO.sub.4),
filtration and evaporation gave a yellow oil (82 g, quantitative)
which was used without further purification. Anal. Calc. for
C.sub.13 H.sub.16O.sub.4: C, 66.09; H, 6.83. Found: C, 67.25; H,
6.92.
[0174] c) Methyl
3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]-
propenoate. To a solution of methyl-3-(Prop-1-yloxy)benzoylacetate
(10 g, 4.2 mmol) in benzene (50 mL) was added
3,4-methylenedioxybenzaldehyde (6.36 g, 4.2 mmol) followed by
piperidine (0.42 mL, 0.42 mmol) and glacial acetic acid (8 drops
approx.). The mixture was refluxed for 2 h. and the volatiles
removed in vacuo to give methyl (Z)-3-(3,4-methylenedio-
xyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate (7.4 g, 48%) as an
off white solid after trituration with methanol (m. p.
122-123.degree. C). Anal. Calc. for C.sub.21H.sub.20O.sub.6: C,
68.47; H, 5.47. Found: C, 68.81; H, 5.49.
[0175] d) Methyl-(1RS,
2SR)-1-(3,4-Methylenedioxyphenyl)-5-(prop-1-yloxy)--
3-oxo-indane-2-carboxylate. Methyl
3-(3,4-methylenedioxyphenyl)-2-[3-(prop-
-1-yloxy)-benzoyl]propenoate (7.4 g, 2.0 mmol) was dissolved in
trifluoroacetic acid (50 mL) at 0.degree. C. and the mixture
stirred at room temperature for 20 min. The trifluoroacetic acid
was removed in vacuo to give the title compound (6.4 g, 87%) as a
white solid after trituration with warm isopropanol m. p.
106-108.degree. C. Anal. Calc. for C.sub.21H.sub.20O.sub.6: C,
68.47; H, 5.47. Found: C, 68.12; H, 5.41.
[0176] e)
Methyl-3-(3,4-Methylenedioxyphenyl)-6-(prop-1-yloxy)-1-oxo-inden-
e-2-carboxylate. Methyl (1RS,
2SR)-1-(3,4-methylenedioxyphenyl)-5-(prop-1--
yloxy)-3-oxo-indane-2-carboxylate (26.2 g, 71 mmol) was dissolved
in toluene (250 mL) and DDQ (dichlorodicyano-quinone) (16.5 g, 71
mmol) was added. The mixture was heated at 80.degree. C. for 2 h.
then cooled, filtered and the solvent removed in vacua. The product
was purified by flash column chromatography on silica gel (eluant:
EtOAc/hexane, 20:80) to give the title compound as an orange solid
(11.3 g, 44%); m.p. 125-126.degree. C. Anal. Calc. for
C.sub.21H.sub.18O.sub.6: C, 68.85; H, 4.95. Found: C, 68.45; H,
4.97.
[0177] f)
Methyl-(1RS)-1-hydroxy-(4-methoxy-2-methoxymethoxyphenyl)-1-3-(3-
,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-carboxylate. To
dry magnesium turnings (1.7 g, 69 mmol) under an argon atmosphere
was added portionwise, a solution of
4-methoxy-2-methoxymethoxybromobenzene (16.8 g, 68 mmol) in 5%
THF/ether (120 mL). The resulting 4-methoxy-2-methoxymethoxyphenyl
magnesium bromide was added to a solution of
methyl-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)-1-oxo-in-
dene-2-carboxylate (18.5 g, 51 mmol) in THF (400 mL) under an argon
atmosphere at 0.degree. C. The resulting mixture was allowed to
warm to room temperature and was stirred for 10 min. The mixture
was partitioned between 3M HCl and EtOAc . The organic extract was
washed successively with H.sub.2O, aqueous NaHCO.sub.3, H.sub.2O
and saturated aqueous NaCl and dried (Na.sub.2SO.sub.4). The
solvent was removed under reduced pressure, and the residue
purified by flash chromatography on silica gel (eluant:
EtOAc/hexane, 10-20%) to afford the title compound as a yellow oil
(24.5 g, 91%). Anal. Calc. for C.sub.30H.sub.30O.sub.9: C, 67.41;
H, 5.66;. Found: C, 67.21; H, 5.66.
[0178] Serparation
[0179] Separation of (+) and (-) methyl
(1RS)-1-Hydroxy-1-(4-methoxy-2-met-
hoxymethoxyphenyl)-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-c-
arboxylate was done on a column of cellulose
tris(3,5-dimethylphenyl carbamate) coated on silica gel (Daicel
Chiralcel OD); retention time for (+) 8.8 min.
[.alpha.].sup.25D=+87.5.degree.(c=0.24, CH.sub.3OH). Retention time
for (-) 14.5 min. [.alpha.].sup.25D+85.9.degree.(c=0.21,
CH.sub.3OH) HPLC data: column Chiralcel OD (DAICEL) 21.2 mm
internal diameter, 250 mm length; solvent Ethanol:Hexane 60:40;
flow rate 10 mL/min.; injection: 1 g of racemate; detection UV=405
nm
[0180] g)
(+)Methyl-(1S,2S,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-
-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. A parr
vessel was charged with (+) methyl
(1RS)-1-hydroxy-3-(4-methoxy-2-methoxymethoxy-
-phenyl)-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-carboxylate
(1 g, 1.8 mmol) dissolved in a small volume of EtOAc (25 mL) and
10% palladium on activated carbon (93 mg). The resulting solution
was stirred under an atmosphere of hydrogen for 120 hours and
filtered. The filtrate was concentrated under reduced pressure and
the product purified by column chromatography on silica gel
(eluant: EtOAc/hexane, 5-10%) to give the 12(g) as a white foam
(0.80 g, 83%). [.alpha.].sup.25D=+105.4.degree.- (c=0.13,
CH.sub.3OH). Anal. Calc. for C.sub.30H.sub.32O.sub.8: C, 69.22; H,
6.20. Found: C, 68.95; H, 6.11.
[0181] h) (+)Methyl-(1S,2S,3S
)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methy-
lenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. To a
solution of methyl-(1S ,2S
,3S)-3-(2-methoxymethyl-4-methoxyphenyl)-1-(3,4-methylened-
ioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.7 g, 1.3 mmol)
in methanol (10 mL) concentrated HCl (0.1 mL) was added and it was
then heated to reflux for 2 h. The solvent was then eliminated
under vacuum and the residue was purified by column chromatography
on silica gel (eluant: EtOAc/hexane, 10-20%) to give the 12(h) as a
colorless glass (0.50 g, 78%).
[.alpha.].sup.25D=+116.0.degree.(c=0.18, CH.sub.3OH). Anal. Calc.
for C.sub.28H.sub.28O.sub.7.multidot.1/2 H.sub.2O: C, 69.27; H,
6.02. Found: C, 69.59; H, 5.99.
[0182] i)
(+)Methyl-(1S,2S,3S)-3-(2-Carboethoxymethoxy-4-methoxyphenyl)-1--
(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. A
solution of methyl-(1S,2S
,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methy-
lenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.1 g, 0.2
mmol) in dry DMF (2 mL) was added to NaH (6 mg, 0.24 mmol) in a
small volume of dry DMF at OOC. The mixture was stirred at
0.degree. C. for 15 min. and ethyl bromoacetate was then added (42
mg, 0.25 mmol). The resulting mixture was stirred at 0.degree. C.
for 1 h. The reaction was then quenched with dilute HCl and
extracted with EtOAc. The EtOAc extract was washed with water then
brine, dried (MgSO.sub.4), filtered and evaporated. The product was
purified by column chromatography on silica gel (eluant:
EtOAc/hexane, 10-15%) to give the 12(i) as a glassy solid (82 mg,
68%).[.alpha.].sup.25D=+116.0.degree.(c=0.45, CH.sub.3OH). Anal.
Calc. for C.sub.32H.sub.34O.sub.9: C, 68.32; H, 6.09. Found: C,
67.98; H, 6.09.
[0183] j) (+)
(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methy-
lenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid. To a
solution of methyl-(1S,2S
,3S)-3-(2-Carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-met-
hylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (20 mg,
0.04 mmol) in dioxane (1 mL) was added 3 M NaOH solution (0.3 mL, 1
mmol). The reaction mixture was heated to reflux for 4 h and after
cooling the solvent was eliminated in vacuo dissolved in water and
acidified with 3N HCl. The resulting precipitate was collected by
filtration and dried to give a white solid (15 mg, 81%); m.p.
99-102 [.alpha.].sup.25D=+38.1.degr- ee.(c=0.22, CH.sub.3OH). Anal.
Calc. for C.sub.29H.sub.28O.sub.9: C, 66.92; H, 5.42. Found C,
67.37; H, 5.32.
EXAMPLE 12A
Preparation of 1-Bromo-4-methoxy-2-methoxymethoxybenzene.
[0184] a) 1-Bromo-2-hydroxy-4-methoxybenzene.
3-Bromo-2-hydroxy-6-methoxyb- enzoic acid [T. de Paulis et. al. J.
Med. Chem., (1985), 28, 1263-1269](5 g, 0.02 mol) was heated in
quinoline (200 mL) at 160.degree. C. for 1 h. On cooling, the
product was partitioned between Et.sub.2O and 3M HCl. The organic
extract was washed with water and brine then dried (MgSO.sub.4),
filtered and evaporated to give the title compound which was
recrystallized from 5% ethyl acetate/hexane (4 g, 97%); m.p.
40-42.degree. C. Anal. Calc. for C.sub.7H.sub.7BrO.sub.2: C, 41.41;
H, 3,48. Found C, 41.39; H, 3.37.
[0185] b) 1-Bromo-4-methoxy-2-methoxymethoxybenzene. To a
suspension of NaH (2.5 g, 0.06 mol) in dry DMF (100 mL) at
0.degree. C. was added solution of
1-bromo-2-hydroxy-4-methoxybenzene (10.6 g, 0.05 mol). After
stirring at 0.degree. C. for 30 min. bromomethyl methyl ether (7.8
g, 0.06 mmol) were dropwise added. The mixture was warmed to room
temperature over 20 min. and then stirred for 2 h, it was then
quenched cautiously by the addition of cold dilute HCl and
extracted with EtOAc. The EtOAc extract was washed successively
with; H.sub.2O, 5% aqueous NaHCO.sub.3, H.sub.2O and finally brine.
After drying (MgSO.sub.4) filtration and evaporation gave liquid.
The product was purified by distillation (85.degree. C., 0.2 mm Hg)
to give the title compound as a colorless oil (13.7 g, 97%).
.sup.1H NMR (CDCl.sub.3) .delta.7.40 (d, 1H, J=8.9 Hz), 6.75 (d,
1H, J=2.8 Hz), 6.46 (dd, 1H, J=8.9, 2.8 Hz), 5.23 (s, 2H), 3.77 (s,
3H), 3.52 (s, 3H).
EXAMPLE 13
(1RS, 2SR, 3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxy-phenyl
-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic
acid. dicyclohexylamine salt
[0186] Methyl
(1RS,2RS,3RS)-3-(2-Hydroxy-4-methoxy-phenyl)-1-(3,4-methylen-
edioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.14 g, 0.29
mmol) in dry DMF (1 ml) was added to NaH (9 mg, 0.38 mmol) in a
small volume of dry DMF. The mixture was stirred at ambient
temperature for 20 min. then 3-bromopropan-1-ol (37 .mu.l, 0.41
mmol) was added. After stirring for 1 h. the product was
partitioned between 3M aqueous HCl and ethyl acetate. The organic
layer was washed with water then brine, then dried (MgSO.sub.4
anhyd.) filtered and evaporated to give an oil. The product was
purified by column chromatography to provide methyl
(1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.g,
65%)(.sup.1H-NMR indicated some epimerization had occurred at C-2).
This material was used without further purification. Methyl (1RS,
2RS, 3RS)-3- [2-(3-Hydroxyprop-1
-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-
-5-(prop-1-yloxy)-indane-2-carboxylate (0.04 g, 0.075 mmol) was
dissolved in methanol (2 ml) and aqueous potassium hydroxide added
(2M, 0.22 ml, 0.44 mmol). The mixture was stirred under reflux
overnight then cooled, diluted with water, acidified with 3M
aqueous hydrochloric acid and extracted with ethyl acetate. The
organic extract was washed with water and brine, dried (MgSO.sub.4
anhydrous), filtered and evaporated to give an oil. The product was
purified by chromatography on silica-gel (eluant: ethyl
acetate/hexane/3% acetic acid) to give 12 mg of free acid which was
converted to its dicyclohexylamine salt. m.p. 110-112.degree.
C.
EXAMPLE 14
(1RS, 2SR,
3RS)-3-[2-(1-Carboxyeth-2-yloxy)-4-methoxy-phenyl]-1-(3,4-methy-
lenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid,
bis-dicyclohexylamine salt
[0187] (1RS, 2SR,
3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,-
4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
(0.07 g, 0.13mmol) was dissolved in dry dichloromethane (0.5 ml)
and Dess-Martin periodinane (0.07 g, 0.17 mmol) added in dry
dichloromethane (1 ml). After 2 h. the product was partitioned
between ether and saturated aqueous sodium carbonate solution
containing sodium thiosulfate. The ether extract was washed with
water then brine, dried (MgSO.sub.4 anhydrous), filtered and
evaporated to give an oil which was used without purification. The
crude product was dissolved in t-butanol (5 ml) and to this was
added a solution of sodium chlorite (18 mg, 0.2 mmol) and sulfamic
acid (21 mg, 0.22 mmol) in water (1.5 ml). After 1 h. stirring at
ambient temperature the product was extracted into ethyl acetate.
The organic layer was washed with water then brine then dried
(MgSO.sub.4 anhyd.) filtered and evaporated to give an oil. The
product was purified by column chromatography on silica-gel
(eluant: ethyl acetate/hexane/3% acetic acid) to give 12 mg of free
acid which was converted to its bis-dicyclohexylamine salt. m.p.
160-162.degree. C. MS (exact mass) M.sup.+: 534.1879 (free di-acid)
(.DELTA.=+1.1 mDa for C.sub.30H.sub.30O.sub.9)
[0188] By the methods given above, the following compounds were
made:
EXAMPLE 15
(1RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylic acid
[0189] m.p. 191-193.degree. C.
[0190] Anal Calcd. for C.sub.23H.sub.18O.sub.3: C, 80.68; H,
5.30.
[0191] Found: C, 80.54; H, 5.33.
EXAMPLE 16
(Trans, Trans)-1,3-Diphenylindane-2-carboxylic acid
[0192] m.p. 164- 165.degree. C.
[0193] MS (m/e): 332 [(M+NH.sub.4).sup.+].
EXAMPLE 17
(1RS, 2RS, 3SR)-1-(4-Hydroxyphenyl)-3-phenylindane-2-carboxylic
acid
[0194] MS (m/e): 331 [(M+H).sup.+].
EXAMPLE 18
(1RS, 2RS, 3SR)-1-(4-Carboxyphenyl)-3-phenylindane-2-carboxylic
acid
[0195] MS (m/e): 359 [(M+H).sup.+].
EXAMPLE 19
(1RS, 2RS, 3SR)-1-(3-Methoxyphenyl)-3-phenylindane-2-carboxylic
acid
[0196] MS (m/e): 362 [(M+NH.sub.4).sup.+].
EXAMPLE 20
(1RS, 2RS, 3SR)-1-(4-Ethylphenyl)-3-phenylindane-2-carboxylic
acid
[0197] m.p. 163 - 164.degree. C.
[0198] MS (m/e): 360 [(M+NH.sub.4).sup.+].
[0199] Anal. Calcd. for C.sub.24H.sub.22O.sub.2: C, 84.18; H,
6.48.
[0200] Found: C, 84.24; H, 6.73.
EXAMPLE 21
(1RS, 3RS)-1,3-Diphenylindane-2-carboxylic acid
[0201] m.p. 220-222.degree. C (dec).(disodium salt).
EXAMPLE 22
(1RS, 2RS,
3SR)-1-(4-But-4-yloxyphenyl)-3-(4-methoxyphenyl)indane-2-carbox-
ylic acid
[0202] .sup.1H NMR (CDCl.sub.3) : .delta.7.26-7.17 (m, 6H);
6.93-6.87 (m, 6H); 4.62 (d, 2H, J=10.1 Hz); 3.96 (t, 2H, J=6.5 Hz);
3.81 (s, 3H); 3.29 (t, 1H, J=10.1 Hz); 1.80-1.73 (m, 2H); 1.54 -
1.45 (m, 2H); 0.98 (t, 3H, J=7.3 Hz).
EXAMPLE 23
(1RS, 2RS,
3SR)-1-(4-Acetamidophenyl)-3-(4-methoxyphenyl)indane-2-carboxyl- ic
acid
[0203] m.p. 231-232.degree. C.
[0204] MS (m/e, rel. int.) : 803-[(2M+1).sup.+, 100].
[0205] Anal. Calcd. for C.sub.25H.sub.23NO.sub.4.multidot.1/2
H.sub.2O: C, 73.12; H, 5.85; N, 3,41. Found: C, 72.92; H, 5.61; N,
3.24.
EXAMPLE 24
(1RS, 2RS,
3SR)-1-(4-Aminophenyl)-3-(4-methoxyphenyl)indane-2-carboxylic acid,
dicyclohexylamine salt
[0206] m.p. 187-190.degree. C.
[0207] MS (m/e, rel. int.): 1076.2 [(2M+1).sup.+, 25].
EXAMPLE 25
(1RS, 2SR,
3SR)-1-(4-Hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-c-
arboxylic acid
[0208] m.p. 94-96.degree. C.
[0209] MS (m/e) : 392.4 [(M+NH.sub.4).sup.+].
EXAMPLE 26
(1RS, 2RS,
3SR)-1-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)indane-2-carbox-
ylic acid
[0210] m.p. 126-128.degree. C.
[0211] MS (m/e, rel. int.) : 807 [(2M+1).sup.+, 35 ]; 403
[(M-H).sup.-, 100].
[0212] Anal. Calcd. for C.sub.25H.sub.24O.sub.5: C, 74.24; H, 5.98.
Found: C, 74.10; H, 5.99.
EXAMPLE 27
(1RS, 2RS,
3SR)-1-(3,4-Methylenedioxyphenyl)-3-(4-methylthioxyphenyl)indan-
e-2-carboxylic acid
[0213] MS (exact mass): (M).sup.+=404.1074 (.DELTA.=+0.8 mDa for
C.sub.24H.sub.20O.sub.4S).
EXAMPLE 28
(1RS, 2SR,
3SR)-5-Methoxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-
indane-2-carboxylic acid
[0214] m.p. 129-131.degree. C.
[0215] MS (m/e): 441.2 [(M+Na).sup.+].
EXAMPLE 29
(1RS, 2SR,
3SR)-1,3-Bis(3,4-methylenedioxyphenyl)-5-hydroxyindane-2-carbox-
ylic acid
[0216] MS (m/e): 436.2 [(M+NH.sub.4).sup.+].
EXAMPLE 30
(1RS, 2SR,
3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(2-methoxy-4,5-meth-
ylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid
[0217] Methyl (1RS, 2RS,
3SR)-5-Hydroxy-3-(4-methoxy-2-methoxymethoxypheny-
l)-1-(2-methoxy-4,5-methylenedioxyphenyl)indane-2-carboxylic acid
was prepared in 23% overall yield from methyl
2-(3-benzyloxy)benzoylacetate according to the method of example
11. The 5-hydroxyl moiety was then propylated according to the
method given in example 12 and this crude material treated
according to the method of example 70 to remove the methoxymethyl
group in 55% yield. The title compound was then obtained following
the procedure given for example 12 in 42% yield. m.p.
188-190.degree. C. Anal. Calc. for C.sub.30H.sub.30O.sub.10: C,
65.45; H, 5.49. Found: C, 65.38; H, 5.49.
EXAMPLE 31
(1RS, 2SR,
3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)1-(3,4-methylenedioxyp-
henyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0218] m.p. 161- 163.degree. C.
EXAMPLE 32
(1RS, 2SR,
3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-
-5-(prop-1-yloxy)indane-2-carboxylic acid
[0219] (exact mass) M.sup.+: 462.1678 (.DELTA.=0.4 mDa for
C.sub.27H.sub.26O.sub.7)
EXAMPLE 33
(1RS, 2SR,
3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-2-(prop-1-yloxy)-4,-
5-methylenedioxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylic
acid
[0220] Anal. Calc. for C.sub.32H.sub.34O.sub.10.multidot.0.5
H.sub.2O: C, 65.41; H, 6.00. Found: C, 65.27;
[0221] H, 5.99, m.p. 196-197.degree. C.
EXAMPLE 34
(1RS, 2SR,
3RS)-1-(2-Carboxymethoxy-4,5-methylene-dioxyphenyl)-3-(4-methox-
yphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0222] MS (DCI NH.sub.3) m/e: 538.2 (M+NH.sub.3).sup.+, 520.2
(M+H).sup.+(exact mass) M.sup.+: 520.1733 (.DELTA.=0.0 mDa for
C.sub.29H.sub.28O.sub.9)
EXAMPLE 35
(1RS, 2SR,
3RS)-1-(3,4-Methylenedioxyphenyl)-3-[2-(prop-1-yloxy)phenyl-5-(-
prop-1-yloxy)indane-2-carboxylic acid
[0223] m.p. 179-180.degree. C.
[0224] MS (DCI CH.sub.4) m/e: 503.2 (M+C.sub.2H.sub.5).sup.+, 474.1
(M+H).sup.+(exact mass) M.sup.+: 474.2034 (.DELTA.=+0.8 mDa for
C.sub.29H.sub.30O.sub.6)
EXAMPLE 36
(1RS, 2SR,
3RS)-3-(2-Hydroxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-
-yloxy)indane-2-carboxylic acid
[0225] m.p. 97-98.degree. C.
[0226] MS (exact mass) M.sup.+: 432.1568 (.DELTA.=+0.5 mDa for
C.sub.26H.sub.24O.sub.6)
EXAMPLE 37
(1 RS, 2SR,
3RS)-3-(2-Carboxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-
-(prop-1-yloxy)indane-2-carboxylic acid
[0227] m.p. 169-170.degree. C.
[0228] Anal. Calc. for C.sub.28H.sub.26O.sub.8.multidot.0.25
H.sub.2O: C, 67.94; H, 5.40. Found: C, 67.75; H, 5.37.
EXAMPLE 38
(1RS, 2SR,
3RS)-3-(2-Benzyloxy-4-methoxyphenyl)-1-(3,4-methylenedioxypheny-
l)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0229] MS (exact mass) M.sup.+: 552.2149 (.DELTA.=-0.1 mDa for
C.sub.34H.sub.32O.sub.7)
EXAMPLE 39
(1RS, 2SR,
3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
dicyclohexylamine salt
[0230] m.p. 182-184.degree. C.
[0231] Anal. Calc. for C.sub.41H.sub.53NO.sub.8: C, 71.59; H, 7.77;
N, 2.04. Found: C, 71.67; H, 7.66; N, 2.42.
EXAMPLE 39A
(+) (1S, 2R,
3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methy-
lenedioxyphenyl)-5-propoxyindane-2-carboxylic acid
[0232] a) Benzyloxyethylbromide
[0233] A mixture of benzyl bromide (103 g, 0.60 moles) and
tetrathylammonium iodide (3.1 g, 0.012 moles) under argon was
heated to 145.degree. C. Ethylene carbonate (84.5 g, 0.96 moles)
was added over 0.75 hr., and the reaction mixture stirred at
145-160.degree. C. for 24 hrs. The mixture was cooled, diluted with
250 ml of deionized water and extracted with 2.times.200 ml of
methylene chloride. The organic extracts were washed with brine,
dried over MgSO.sub.4, and concentrated in vacuo. Distillation gave
90 g (70%) of product as a light yellow liquid (b.p. 80-85.degree.
C., 0.5mm).
[0234] b) 1-Bromo-2-(2-benzyloxyeth-1-yloxy)-4-methoxybenzene
[0235] A mixture of 1-bromo-2-hydroxy-4-methoxy benzene (68.3 g,
0.336 moles), anhydrous potassium carbonate (51.2 g 0.37 moles) and
0.5L of N,N-dimethylformamide was heated to 65.degree. C.
Benzyloxyethylbromide (76.0 g, 0.353 moles) was added dropwise over
0.5 hr. After stirring for 1.5 hr. at 65.degree. C., the reaction
mixture was cooled and filtered. The filtrate was diluted with 1L
of deionized water, and extracted with 3.times.0.5L ethyl acetate.
The organic extracts were washed with brine, dried over MgSO.sub.4,
and concentrated in vacuo. Distillation gave 93 g (83%) of product
as a yellow liquid (b.p. 170-175.degree. C., 0.5 mm).
[0236] c)
Methyl(1SR)-1-hydroxy-3-[2-benzyloxyeth-1-yloxy)-4-methoxyphenyl-
]-1-(3,4methylene dioxyphenyl)-5-propoxyindene-2-carboxylate
[0237] A solution of
1-bromo-2-(2-benzyloxyeth-1-yloxy)-4-methoxybenzene (161 g, 0.478
moles) and 1.6L of tetrahydrofuran @ -70.degree. C. under argon was
treated with n-butyl lithium (190 mL, 2.5 m, 0.478 moles), followed
by magnesium bromide etherate (132 g, 0.512 moles). After stirring
for 0.5 hr., a solution of methyl-3-(3,4-methylenedioxyphenyl)-5-
-propoxy-1-oxo-indene-2-carboxylate (1 17 g, 0.32 moles) in 1L of
tetrahydrofuran was added over 0.5 hr. The reaction mixture was
stirred for 1 hr. at -70.degree. C., and quenched by addition of
aqueous ammonium chloride. The mixture was extracted with
3.times.1L of methyl t-butylether. The organic extracts were washed
with brine, dried over MgSO.sub.4, and concentrated in vacuo to
give 240 g of crude product. Chromatography on 1.5 Kg silica gel
using a hexane: methylene chloride: ethyl acetate gradient gave 175
g (88%) of light orange oil.
[0238] d) Methyl (1SR, 2SR,
3SR)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphen-
yl-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylate
[0239] A mixture of methyl
(1SR)-1-hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-
-methoxyphenyl]-1-(3,4-methylenedioxy
phenyl)-5-propoxyindene-2-carboxylat- e (88 g, 0.141 moles) 10%
palladium on carbon (21 g), 0.65L of absolute ethanol and 0.65L of
ethylacetate was hydrogenated at 50 psi, 55.degree. C. for 48 hrs.
The catalyst was filtered off, and the filtrate concentrated in
vacuo to give an amorphous glass. Crystallization from 350 mL of
absolute ethanol gave 59.5 g (81%) of white solid; m.p.
165-168.degree. C.
[0240] Chiral Resolution
[0241] Separation of (+) and (-) methyl (1SR, 2SR,
3SR)-3-[2-(2-hydroxyeth-
-1-yloxy)4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-c-
arboxylate was accomplished using an amylose tris
(3,5-dimethylphenylcarba- mate) coated on silica gel (Daicel
Chiralpak AD). The mobile phase consisted of 50:40:10 hexane:
isopropanol: chloroform. The retention times of the enantiomers
were 4.7 min (+isomer), and 9.2 min (-isomer), using a
4.6.times.250 mm column at 1.0 ml/min.
[0242] e) (+) (1S, 2R,
3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1--
(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylic acid
[0243] To a solution of (+) methyl (1S, 2S,
3S)-3-[2-(2-hydroxyeth-1-yloxy-
)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxyl-
ate (69.3 g, 0.133 moles) in 1.4L of methanol and 0.14L of
deionized water was added 50% aqueous sodium hydroxide (0.059L,
0.74 moles). The reaction mixture was refluxed for 16 hrs. After
concentrating the mixture in vacuo, the slurry was diluted with 1L
of deionized water, and acidified to pH 2 with 3 N HCl. The mixture
was extracted with 3.times.500 mL of methyl-t-butyl ether. The
organic extracts were combined, washed with brine, dried of
MgSO.sub.4, and concentrated in vacuo. The resulting oil was
crystallized from 400 mL of isopropanol to give 40.7 g (60%) of
white solid; m.p. 119.degree.-122.degree. C.;
[.alpha.].sub.D24.degree. C.=+60.4.degree.(C=0.5, CH.sub.3OH).
[0244] Formation of the hemiethylenediamine salt gave a white
crystalline solid; m.p. 177-179.degree. C.;
[.alpha.].sub.D24.degree. C.+70.0.degree.(C=0.5, CH.sub.3OH).
EXAMPLE 40
(1RS,2SR,3RS)-3-(2-Ethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl]-5--
(prop-1-yloxy)indane-2-carboxylic acid
[0245] Anal. Calc. for C.sub.29H.sub.30O.sub.7: C, 71.01; H, 6.16;
Found: C, 70.71; H, 6.01.
EXAMPLE 41
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(prop-1-yloxy)phenyl]-1-(3,4-methylenedioxy-
phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0246] Anal. Calc. for C.sub.30H.sub.32O.sub.7: C, 71.41; H, 6.39;
Found: C, 71.43; H, 6.31.
EXAMPLE 42
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(prop-2-yloxy)phenyl]-1-(3,4-methylenedioxy-
phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0247] m.p. 75-79.degree. C.
EXAMPLE 43
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(2-methylprop-1-yloxy)phenyl]-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0248] m.p. 85-89.degree. C.
EXAMPLE 44
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(3-methylbut-1-yloxy)phenyl]-1-(3,4-methyle-
nedioxyphenyl)-5-(prop -1-yloxy)indane-2-carboxylic acid.
dicylohexylamine salt
[0249] m.p. 150-155.degree. C.
EXAMPLE 45
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(3-pyridylmethoxyphenyl]-1-(3,4-methylenedi-
oxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
[0250] Anal. Calc. for
C.sub.33H.sub.31NO.sub.7.multidot.0.5H.sub.2O: C, 71.02; H, 5.78;
N, 2.51; Found: C, 71.02; H,5-53; H, 2.30.
EXAMPLE 46
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(4-pyridylmethoxyphenyl]-1-(3,4-methylenedi-
oxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
[0251] Anal. Calc. for
C.sub.33H.sub.31NO.sub.7.multidot.0.5H.sub.2O: C, 71.02; H, 5.78;
N, 2.51; Found: C, 70.89; H, 5.59; H, 2.37.
EXAMPLE 47
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(2-pyridylmethox)phenyl]-1-(3,4-methylenedi-
oxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0252] m.p. 153-155.degree. C.
EXAMPLE 48
(1RS,2SR,3RS)-3-[2-(Hept-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyph-
enyl-5-(prop-1-yloxy)indane-2-carboxylic acid
[0253] m.p. 70-73.degree. C.
EXAMPLE 49
(1RS, 2SR,
3RS)-3-[4-Methoxy-2-(5-tetrazolylmethoxy)-phenyl]-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid.
[0254] m.p. 102-105.degree. C.
EXAMPLE 50
(1RS,2SR,3RS)-3-(2-Cyanomethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphen-
yl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0255] m.p. 199-201.degree. C.
EXAMPLE 51
(1RS,2SR,3RS)-3-(2-Carboxamidomethoxy-4-methoxyphenyl)-1-(3,4-methylenedio-
xyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0256] Anal. Calc. for
C.sub.29H.sub.29NO.sub.8.multidot.0.5C.sub.4H.sub.8- O: C, 67.02;
H, 5.99; N, 2.52; Found: C, 67.76; H, 5.96; H, 2.56.
EXAMPLE 52
(1RS, 2SR, 3
SR)-5-Acetamido-1,3-bis(3,4-methylenedioxyphenyl)indane-2-car-
boxylic acid.
[0257] MS m/e : 460 [(M+H).sup.+].
EXAMPLE 53
(1RS, 2SR,
3SR)-5-Amino-1,3-bis(3,4-methylenedioxyphenyl)indane-2-carboxyl-
ate, dicyclohexylamine salt.
[0258] MS m/e: 418 [(M+H).sup.+].
EXAMPLE 54
(1RS,2SR,3RS)-3-[2-(3-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenediox-
yphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0259] a) Ethyl 3-[tri-(but-1-yl)stannyl)benzoate
[0260] Ethyl 3-bromobenzoate (2.0 g, 8.7 mmol),
hexabutyl-distannane (5.51 ml, 10.9 mmol),
tetakis(triphenyl-phosphine)palladium(0) (0.08 g, 0.07 mmol) and
palladium (II) acetate (0.19 g, 0.85 mmol) were mixed in dry
toluene (25 ml) and refluxed for 72 h under argon. The solvent was
removed in vacuo and the residue purified by column chromatography
on silica gel (eluant:hexane). The title compound was obtained as a
colorless oil (1.1 g, 30%).
[0261] b) Methyl (1RS,2RS,3R
S)-3-[2-(3-carbomethoxyphenyl)-4-methoxypheny-
l]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
[0262] Methyl (1RS, 2SR,
3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyph-
enyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
(0.118 g, 0.19 mmol), lithium chloride (0.058 g, 1.37 mmol),
tetrakis(tri-phenylphosphine)-palladium(0) (0.018 g, 0.016 mmol)
and ethyl 3-[tri-(butyl-1-yl)stannyl]benzoate (0.253 g, 0.58 mmol)
were mixed in dry dimethylformamide (5 ml) and refluxed for 24 h.
The product was filtered through celite and the celite washed with
ethyl acetate. The combined filtrate was evaporated in vacuo and
was shown to be a mixture of two components by TLC. Purification by
column chromatography on silica-gel gave a less polar fraction:
methyl (1RS, 2SR,
3SR)-3-[2-(but-1-yl)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(pro-
p-1-yloxy)indane-2-carboxylate (0.038 g) which was obtained as a
colorless oil. The title compound was the more polar component
(0.08 g) which while contaminated with tin residues (.sup.1H-NMR)
was used without further purification.
[0263] c) (1RS, 2SR,
3RS)-3-[2-(3-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid
[0264] Methyl (1RS, 2SR,
3RS)-3-[2-(3-Carbomethoxyphenyl)-4-methoxyphenyl]-
-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
(0.08 g, crude) was dissolved in propan-2-ol (1 ml) and aqueous
sodium hydroxide (1M, 1 ml ,1 mmol) added. The mixture was refluxed
for 12 hr. then cooled, diluted with water, acidified with
3M-aqueous hydrochloric acid and extracted with ethyl acetate (3x).
The combined organic extract was purified by column chromatography
on silical-gel (eluant: 30% EtOAc/hexane/5%AcOH) to give the title
compound as a colorless solid (20 mg)
[0265] m.p. 257-268.degree. C.
EXAMPLE 55
(1RS, 2SR,
3SR)-3-[2-(But-1-yl)-4-methoxyphenyl)-1-(3,4-methylenedioxyphen-
yl)-5-(prop-1-yloxy)indane-2-carboxylic acid, dicyclohexylamine
salt
[0266] Methyl (1RS, 2SR,
3SR)-3-[2-(But-1-yl)-4-methoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylate (0.038 g,
0.074 mmol) was dissolved in propan-2-ol (1 ml) and aqueous sodium
hydroxide (1M, 0.75 ml,0.75 mmol) added. The mixture was refluxed
for 12 hr. then cooled, diluted with water, acidified with
3M-aqueous hydrochloric acid and extracted with ethyl acetate (3x).
The combined organic extract was purified by column chromatography
on silica-gel (eluant: 30% EtOAc/hexane then 30% EtOAc/hexane/5%
AcOH). Conversion of the product to its dicyclohexylamine salt gave
the title compound.
[0267] m.p. 179-182.degree. C.
[0268] Anal. Calc. for C.sub.41H.sub.53NO.sub.8: C, 71.59; H,
7.77;
[0269] N, 2.04. Found: C, 71.67; H, 7.66; N, 2.42.
EXAMPLE 56
(1RS, 2SR,
3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)--
5-(prop-1-yloxy)indane-2-carboxylic acid
[0270] a) Methyl (1RS, 2RS,
3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methy-
lenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
[0271] To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) and
tetrakis(triphenylphosphine)-palladium(0) (24 mg, 0.02 mmol) in dry
dioxane (3 mL) was added a solution of Methyl (1RS , 2RS ,
3RS)-3-(4-Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedi-
oxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol)
and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol) in dioxane (1
mL). The mixture was refluxed under Argon for 17 h, cooled to room
temperature, diluted with ethyl acetate (5 ml) and the resulting
solution washed sequentially with brine and water. The organic
layer was dried (MgSO.sub.4 anhydrous), filtered through a short
pad of silica gel and concentrated in vacuo to yield an oil. The
product was purified by flash column chromatography (silica gel,
gradient elution from hexanes to 10 % ethyl acetate/hexanes) to
afford the title compound as a white solid. (92 mg, 86%).
[0272] b)
(1RS,2SR,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxy-
phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid To a solution of
Methyl (1RS, 2RS,
3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-
-5-(prop-1-yloxy)indane-2-carboxylate (80 mg, 0.12 mmol) in dioxane
(2 mL) was added 1M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting
mixture was heated to reflux for 48 h, then concentrated under
reduced pressure. The residue was partitioned between dilute
aqueous HCl and ethyl acetate. The ethyl acetate extract was washed
with water and dried (MgSO.sub.4 anhydrous). The solvent was
removed in vacuo and the residue purified by flash column
chromatography (silica gel, 20% ethyl acetate/hexane containing 5%
of acetic acid) to afford the title compound (36 mg, 46%).
[0273] m.p. 199-200.degree. C.
[0274] .sup.1H NMR (CDCl.sub.3) .delta.7.18-7.09 (m, 6H); 6.85 (dd,
1H, J=8.6, 2.1 Hz); 6.71-6.65 (m, 6H),6.36 (b s, 1H), 5.85 (s, 2H),
4.59 (d, 1H, J=10.2 Hz); 4.31 (d, 1H, J=10.2 Hz); 3.75 (t, 2H,
J=7.3 Hz); 3.73 (s, 3H); 3.14 (dd, 1H, J=10.2, 10.2 Hz); 1.68
(sextet, 2H, J=7.3 Hz); 0.93 (t, 3H, J=7.3 Hz).
[0275] MS m/e: 540 (M+NH.sub.4).sup.+.
[0276] Anal. Calc. for C.sub.33H.sub.30O.sub.6.multidot.3/4
H.sub.2O: C, 73.93;
[0277] H, 5.90. Found: C, 74.12, H, 5.80.
EXAMPLE 57
(1RS, 2SR,
3SR)-3-[2-[(E)-2-Carboxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-met-
hylenedioxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylic acid
[0278] a) Methyl (1RS, 2SR,
3SR)-3-[2-[(E)-2-carbomethoxy-ethen-1-yll-4-me-
thoxyphenyl]-1-(3,4-methylene-dioxyphenyl)-5-(prop-1-yloxy)indane-2-carbox-
ylate.
[0279] 1,3-bis(diphenylphosphino)propane (0.066 mmol),
tris(dibenzylideneacetone)-dipalladium(0) (24 mg, 0.026) and
bis(triphenylphosphine)palladium(II) choride (18 mg, 0.026 mmol),
were dissolved in a 4:1 mixture of triethylamine/acetonitrile (5
mL) under argon. After 10 min at room temperature, a solution of
methyl (1RS, 2SR,
3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedi-
oxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (160 mg, 0.26 mmol)
and methyl acrylate (679 mg, 7.89 mmol) was added in the above
solvent mixture (3 mL). The reaction mixture was heated to reflux
under argon for 20 h, cooled to room temperature and a small
aliquot analyzed by .sup.1H NMR, which showed no reaction had taken
place. Palladium(II) acetate (6 mg, 0.025 mmol) and methyl acrylate
(679 mg, 7.89 mmol) in dry DMF (5 mL) were then added. The reaction
mixture was heated to reflux overnight. On cooling the solution was
filtered through a short column of silica gel and concentrated to
yield an oil. The crude product was purified by flash column
chromatography ( silica gel, gradient elution: 10 % to 20% ethyl
acetate/hexanes to afford the title compound as a tan solid. (87
mg, 62%).
[0280] .sup.1H NMR (CDCl.sub.3) : .delta.8.17 (d, 1H, J=15.7 Hz);
7.44 (d, 1H, J=8.7 Hz), 7.11-7.07 (m, 2H); 6.90-6.70 (m, 6H), 6.42
(d, 1H, J=15.7 Hz); 5.94 (b s, 2H), 5.04 (d, 1H, J=7.5 Hz); 4.75
(d, 1H, J=7.6 Hz); 3.89 (t, 2H, J=6.7 Hz); 3.85 (s, 3H); 3.85 (dd,
1H, J=7.5, 7.4 Hz); 3.83 (s,3H); 2.96 (s,3H), 1.79 (sextet, 2H,
J=6.7 Hz); 1.03 (t, 3H, J=6.7 Hz).
[0281] b) (1RS, 2SR,
3SR)-3-[2-[(E)-2-Carboxyethen-1-yl]-4-methoxyphenyl]--
1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid.
[0282] To a solution of methyl (1RS, 2SR,
3SR)-3-[2-[(E)-2-carbomethoxyeth-
en-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)ind-
ane-2-carboxylate (80 mg, 0.15 mmol) in dioxane (2 ml) was added 1
N NaOH (0.5 ml, 0.5 mmol). The resulting mixture was heated to
reflux for 3 h, then cooled and concentrated under reduced
pressure. The residue was partitioned between dilute aqueous HCl
and ethyl acetate. The ethyl acetate extract was washed with water
and dried (MgSO.sub.4 anhydrous). The solvent was removed in vacuo
and the title compound was obtained as a white solid (73 mg,
96%).
[0283] .sup.1H NMR (CDCl.sub.3) : .delta.8.32 (d, 1H, J=15.6 Hz);
7.24-6.55 (m, 9H); 6.29 (d, 1H, J=15.6 Hz); 5.94 (b s, 2H), 5.18
(d, 1H, J=9.9 Hz); 4.69 (d, 1H, J=9.9 Hz); 3.85 (s, 3H); 3.84 (t,
2H, J=6.9 Hz); 2.94 (dd, 1H, J=9.9, 9.9 Hz); 1.79 (sextet, 2H,
J=6.9 Hz); 1.00 (t, 3H, J=6.9 Hz).
[0284] MS m/e : 517 [(M+H).sup.+].
[0285] Anal. Calc. for C.sub.30H.sub.28O.sub.8: C, 69.76; H, 5.46.
Found: C, 69.73, H, 5.26.
EXAMPLE 58
(1RS, 2SR,
3SR)-3-[2-(2-Carboxyeth-1-yl)-4-methoxyphenyl]-1-(3,4-methylene-
dioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid.
[0286] To a solution of (1RS, 2SR,
3SR)-3-[2-[(E)-2-carboxy-ethen-1-yl]-4-- methoxyphenyl]-1-
(3,4-methylenedioxy-phenyl)-5-(prop- 1 -yloxy)indane-2-carboxylic
acid (43 mg, 0.08 mmol) in ethanol (5 mL) was added 10% palladium
on activated carbon (40 mg). The resulting suspension was stirred
overnight under an atmosphere of hydrogen then filtered through a
pad of celite. The filtrate was concentrated under reduced pressure
to afford the title compound (35 mg, 82%) as a white solid.
[0287] .sup.1H NMR (CDCl.sub.3): .delta.6.99 (d, 1H, J=8.6 Hz);
6.78-6.66 (m, 7H); 6.23 (b s, 1H); 5.88-5.87 (m, 2 H); 4.88 (d, 1H,
J=9.7 Hz); 4.54 (d, 1H, J=9.7 Hz); 3.72 (s, 3H); 3.70 (t, 2H, J=7
Hz); 2.98-2.90 (m, 1H); 2.68-2.51 (m, 2H); 1.65 (sextet, 2H, J=7.0
Hz); 0.89 (t, 3H, J=7.0 Hz). MS (exact mass) M.sup.+: 518.1930
(D=+1.1 mDa for C.sub.27H.sub.26O.sub.7- )
[0288] By the methods given above in Examples 54 to 58, the
following compounds were made.
EXAMPLE 59
(1RS,2SR,3RS)-3-(2-Carboxymethylthio-4-methoxyphenyl)-1-1-(3,4-methylenedi-
oxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0289] m.p. 242-246.degree. C. (dec).
EXAMPLE 60
(1RS,2SR,3SR)-3-[4-Methoxy-2-(prop-2-en-1-yl)phenyl]-1-(3,4-methylenedioxy-
phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0290] m. p. 126-127.degree. C. (exact mass) M.sup.+: 486.2021
(.DELTA.=+2.1 mDa for C.sub.30H.sub.30O.sub.6)
EXAMPLE 61
(1RS,2SR,3SR)-3-[4-Methoxy-2-(prop-1-yl)phenyl]-1-(3,4-methylenedioxypheny-
l)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0291] m.p. 155-156.degree. C.
[0292] Anal. Calc. for C.sub.30H.sub.32O.sub.6: C, 73.75; H, 6.60.
Found: C, 73.45, H, 6.43.
EXAMPLE 62
(1RS,2SR,3RS)-3-[2-Carboxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-
-(prop-1-yloxy)indane-2-carboxylic acid,
[0293] Anal. Calc. for C.sub.28H.sub.26O.sub.8: C, 68.56; H, 5.34.
Found: C, 68.61, H, 5.58.
EXAMPLE 63
(1RS,2SR,3
SR)-3-[2-(2-Hydroxyethyl)-4-methoxyphenyl]-1-(3,4-methylenediox-
yphenyl)-5-(prop-1 -yloxy)indane-2-carboxylic acid
[0294] (exact mass) M.sup.+: 490.1994 (.DELTA.=+0.3 mDa for
C.sub.29H.sub.30O.sub.7)
EXAMPLE 64
(1RS, 2SR, 3
SR)-3-(2-Carboxymethyl-4-methoxyphenyl)-1-(3,4-methylenedioxy-
phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0295] (exact mass) M.sup.+: 504.1788 (D=-0.4 mDa for
C.sub.29H.sub.28O.sub.8)
EXAMPLE 65
(1RS, 2SR, 3SR)-3-[2-(3-Hydroxyprop-1-yl)-4-methoxy-phenyl]- 1 -(
3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid
[0296] MS (exact mass) M.sup.+: 504.2143 (.DELTA.=+0.5 mDa for
C.sub.30H.sub.32O.sub.7)
EXAMPLE 66
(1RS, 2SR, 3
SR)-5-(4-Carboxyphenyl)-3-bis(3,4-methylenedioxyphenyl)1-inda-
ne-2-carboxylic acid.
[0297] m.p. 230-231.degree. C.
EXAMPLE 67
(1RS, 2SR,
3SR)-5-(4-Benzyloxyphenyl)-1,3-bis(3,4-methylenedioxyphenyl)ind-
ane-2-carboxylic acid.
[0298] m.p. 105-106.degree. C.
EXAMPLE 68
(1RS, 2SR, 3SR)-5-(4-Hydroxyphenyl)-1 ,3-bis(3
,4-methylenedioxyphenyl)ind- ane-2-carboxylic acid.
[0299] MS m/e: 512 [(M+NH.sub.4).sup.+].
EXAMPLE 69
(trans,
trans-1,3,5-tris(3,4-methylenedioxyphenyl)indane-2-carboxylic
acid.
[0300] Anal. Calc. for C.sub.31H.sub.22O.sub.8.multidot.5/8
H.sub.2O: C, 69.76; H, 4.39. Found: C, 69.81, H, 4.46.
EXAMPLE 70
(1RS,
3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(p-
rop-1-yloxy)indane.
[0301] a) (1RS,
3RS)-3-[(2-Methoxymethoxy)-4-methoxyphenyl)]-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)indane.
[0302] A solution of (1RS, 2SR,
3RS)-3-[2-(methoxymethoxy)-4-methoxyphenyl-
]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid (0.2 g, 0.39mmol) in dichloromethane (4ml) and pyridine (28
.mu.l, 1.6 mmol) was cooled to 0.degree. C. under argon. To this
solution was added thionyl chloride (60 .mu.l 0.8 mmol). The
mixture was allowed to warm to ambient temperature over 20 min. and
the volatiles removed in vacuo. The residue was redissolved in
toluene and evaporated in vacuo (twice). The residue was dissolved
in dichloromethane (4 ml) and triethylamine (250 .mu.l) added. To
this solution at room temperature under argon was added
2-mercaptopyridine-N-oxide (120 mg, 0.8 mmol) dissolved in
dichloromethane (1 ml). After stirring for 20 min at room
termperature t-butylthiol (450 .mu.l, 4 mmol) was added and the
mixture irradiated for 20 min (150 watt spotlight). The volatiles
were removed in vacuo and the product partitioned between ethyl
acetate and 3M-aq. HCl. The organic extract was washed with water,
sat. aq. NaHCO.sub.3 solution and finally brine. After drying
(MgSO.sub.4 anhydrous), the product was filtered and evaporated.
Purification by column chromatography gave the title compound
(0.075 g, 41%). .sup.1H NMR (CDCl.sub.3) : .delta.7.13 (d, 1H,
J=8.5 Hz); 6.83 (d, 1H, J=8.3 Hz), 6.79-6.69 (m, 5H), 6.54 (dd, 1H,
J=8.5, 2.5 Hz), 6.51 (br s, 1H), 5.92 (br, s, 2H) 5.18 (d, 1H,
J=6.7 Hz, ), 5.15 (d, 1H, J=6.7 Hz), 4.66 (dd, J=10.5, 7.6 Hz, 1H,
J=6.7 Hz), 4.22 (dd, 1H, J=10.5, 7.4 Hz), 3.81 (m, 2H), 3.80 (s,
3H), 3,43 (s, 3H), 2.90-2.83 (m, 1H), 2.06-1.98 (m, 1H), 1.73
(sextet, 1H, J=7.1 Hz), 0.92 (t, 3H, J=7.1 Hz).
[0303] b) (1RS, 3RS )-3-(2-Hydroxy-4-methoxyphenyl)-
1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
[0304] To a solution of (1RS,
3RS)-3-[(2-methoxymethoxy)-4-methoxyphenyl)]-
-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.075 g, 0.16
mmol) in methanol (5 ml) was added 4-5 drops of 6M-HCl and the
mixture refluxed for 1.5 h under argon. The solvent was removed in
vacuo and the product partitioned between EtOAc and water. The
organic extract was washed with water then sat. aq. NaHCO.sub.3
solution and finally brine. After drying (MgSO.sub.4 anhydrous)
filtration and evaporation gave the title compound (0.064 g,
94%).
[0305] .sup.1H NMR (CDCl.sub.3): .delta.7.11 (d, 1H, J=8.4 Hz),
6.87 (d, 1H, J=7.8 Hz), 6.77-6.74 (4 H, m), 6.61 (br s, 1H), 6.50
(dd, 1H, J=8.4, 2.5 Hz), 6.42 (d, 1H, J=2.5 Hz), 5.94 (d, 1H J=1.2
Hz), 5.93 (d, 1H, J=1.2 Hz), 4.74 (s, 1H), 4.43 (dd, 1H, J=10.4,
7.6 Hz), 4.20 (dd, 1H, J=10.7, 7.3 Hz), 3.82 (t, 2H, J=6.7 Hz),
3.79 (s, 3H), 2.89-2.82 (m, 1H), 2.15-2.08 (m, 1H), 1.77-1.71
(sextet, 2H, J=7.2 Hz), 0.99 (t, 3H, J=2.5 Hz). MS (exact mass)
M+Found: 418.1782 (.DELTA.=-0.2 mDa for
C.sub.26H.sub.26O.sub.5).
EXAMPLE 71
(1RS,2RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl-
)-5-(prop-1-yloxy)indane
[0306] To a slurry of sodium hydride (5 mg, 0.21 mmol) in
dimethylformamide (0.5 ml) was added (1RS,
3RS)-3-(2-hydroxy-4-methoxyphe-
nyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.058 g,
0.14 mmol) at ice-bath temperature under argon. After stirring for
15 min, ethyl bromoacetate (50 .mu.l, 0.2 mmol) was added and the
solution stirred for 1 h at room temperature. The product was
partitioned between ethyl acetate and 3M aq HCl. The organic
extract was washed with water, sat. aq. NaHCO.sub.3 solution and
finally brine. After drying (MgSO.sub.4 anhydrous) filtration and
evaporation followed by chromatography gave (1RS ,
3RS)-3-(2-carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenediox-
yphenyl)-5-(prop-1-yloxy)indane (0.041 g). The product was
dissolved in hot ethanol (10 ml) and 1 M aq. NaOH added (1 ml). The
mixture was refluxed for 1 h then cooled, acidified with 6M-aqueous
HCl and extracted with ethyl acetate. After evaporation the residue
was crystallized from ethyl acetate/hexane to give the title
compound (0.035 g, 93%). m.p. 177-178.degree. C.
[0307] .sup.1H NMR (CDCl.sub.3): .delta.7.18 (d, 1H, J=8.5 Hz),
6.87 (d, 1H, J=8.4 Hz), 6.88-6.71 (4H, m), 6.56 (dd, 1H, J=8.4, 2.3
Hz), 6.53 (br. s, 1H), 6.41 (d, 1H, J=2.3 Hz), 5.91 (br. s, 2H),
4.68-4.60 (m, 3H), 4.61 (dd, 1H, J=10.7, 7.2 Hz), 3.83-3.80 (m,
2H), 3.81 (s, 3H), 2.86 (dt, 1H, J=12.4, 7.2 Hz), 2.10-1.98 (m,
1H), 1.73 (sextet, 2H, J=7.2 Hz), 0.98 (t, 3H, J=7.4 Hz). MS (exact
mass) M+=476.1829 (.DELTA.=+0.6 mDa for
C.sub.28H.sub.28O.sub.7).
EXAMPLES 72-120
The following compounds were prepared by the procedures given
above.
[0308] (1RS, 2SR, 3S R)-
1-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)ind- ane-2-carboxylic
acid, m.p. 197-198.degree. C.;
[0309] (1RS, 2SR,
3SR)-1-(4-Ethoxyphenyl)-3-(3,4-methylenedioxyphenyl)inda-
ne-2-carboxylic acid, m.p. 169-170.degree. C.;
[0310] (1RS, 2SR,
3SR)-5-Carboxy-1,3-bis(3,4-methyl-enedioxyphenyl)indane--
2-carboxylic acid, m.p. 112-115.degree. C.;
[0311] (1RS, 2SR, 3SR)-3-(4-Methoxyphenyl)-
1-(3,4-methylenedioxyphenyl)-5-
-(prop-2-en-1-yloxy)indane-2-carboxylic acid. Anal. Calc. for
C.sub.27H.sub.24O.sub.6.multidot.5/8 H.sub.2O: C, 71.16; H, 5.58.
Found: C, 71.31; H, 5.33;
[0312] (1RS, 2SR,
3RS)-3-(2,4-Dimethoxyphenyl)-5-hydroxy-1-(3,4-methylened-
ioxyphenyl)indane-2-carboxylic acid, m.p. 110-113.degree. C.;
[0313] (1RS, 2SR,
3SR)-3-[5-(2,3-Dihydro)benzofuranyl]-5-hydroxy-1-(3,4-me-
thylenedioxyphenyl)indane-2-carboxylic acid, m.p. 225-228.degree.
C.;
[0314] (1RS, 2SR,
3RS)-5-Hydroxy-3-(3,4-methylenedioxyphenyl)-1-(2,4,6-tri-
methoxyphenyl)indane-2-carboxylic acid, m.p. 225-226.degree.
C.;
[0315] (1RS, 2SR,
3SR)-1-[5-(2,3-Dihydro)benzofuranyl]-3-(4-methoxyphenyl)-
indane-2-carboxylic acid, m.p. 186-190.degree. C.;
[0316] (1RS, 2SR, 3RS)-1-[3,4-(1,2-Ethylenedioxy)phenyl]-3-(4-5
methoxyphenyl)indane-2-carboxylic acid, m.p. 178-181.degree.
C.;
[0317] (1RS, 2SR,
3SR)-5-Hydroxy-3-(3,4-methylenedioxyphenyl)-1-(4-methoxy-
phenyl)indane-2-carboxylic acid, m.p. 124-127.degree. C.;
[0318] (1RS, 2SR,
3RS)-5-Hydroxy-3-(4-methoxyphenyl)-1-(2-methoxy-4,5-meth-
ylenedioxyphenyl)indane-2-carboxylic acid, m.p. 236-239.degree.
C.;
[0319] (1RS, 2SR,
3SR)-1-(3,4-Methylenedioxyphenyl)-3-(4-methoxyphenyl)-5--
(propyl-1-yloxy)indane-2-carboxylic acid, m.p. 132-133.degree.
C.;
[0320] (1RS, 2SR,
3RS)-5-Methoxy-3-(4-methoxyphenyl)-1-(2-methoxy4,5-methy-
lenedioxyphenyl)indane-2-carboxylic acid, m.p. 149-150.degree.
C.;
[0321] (1RS, 2SR,
3RS)-3-[2-(2'-Carboxyphenoxy)-4-methoxyphenyl]-1-(3,4-me-
thylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, m.p.
245-247.degree. C.;
[0322] (1RS, 2SR,
3RS)-3-[2-(2'-Carboxyphenoxy)-5-chloro-4-methoxyphenyl]--
1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid, m.p.. 199-201.degree. C.;
[0323] (1RS, 2SR,
3RS)-3-[2-Carboxymethoxy-4-methoxyphenyl-3-5-hydroxy-1-(-
3,4-methylenedioxyphenyl) indane-2-carboxylic acid, m.p.
182-185.degree. C.
[0324] (1RS, 2SR,
3RS)-5-(But-1-yloxy)-3-(2-carboxymethoxy-4-methoxyphenyl-
)-1-(3,.sup.4-methylenedioxyphenyl) indane-2-carboxylic acid, m.p.
211-219.degree. C.
[0325] (1RS, 2SR, 3RS)-5-Butyl-3-
(2-carboxymethoxy-4-methoxyphenyl)-1-(3,- 4-methylenedioxyphenyl)
indane-2-carboxylic acid, .m.p 176-177.degree. C.;
[0326] (1RS, 2SR,
3RS)-3-[2-(4'-Methoxyphenyl)-4-methoxyphenyl]-1-(3,4-met-
hylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, m.p.
147- 148.degree. C.;
[0327] (1RS, 2RS,
3RS)-1-(2-Carboxymethoxy-4-methoxyphenyl]-3-(3,4-methyle-
nedioxyphenyl)-4-(prop-1-yloxy)indane-2-carboxylic acid m.p.
201-206.degree. C.;
[0328] (1RS, 2SR,
3SR)-3-[2-(3'-Aminopropyl)-4-methoxyphenyl]-1-(3,4-methy-
lenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid. (exact
mass) M.sup.+: 503.2290 (.DELTA.=+1.8 mDa for
C.sub.30H.sub.33O.sub.6N);
[0329] (1RS, 2SR, 3RS)-5-Methoxy-
1-(2-methoxy-3,4-methylenedioxyphenyl)-3-
-(4-methoxyphenyl)indane-2-carboxylic acid m.p. 148-149.degree.
C.;
[0330] (1RS, 2SR,
3RS)-3-[2-(4'-Methoxy-2'-hydroxyphenyl)4-methoxyphenyl]--
1-(3,.sup.4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid, m.p. 199-200.degree. C.;
[0331] (1RS, 2RS,
3RS)-3-(2-Carboxymethoxy-4-isopropyloxyphenyl)-1-(3,4-me-
thylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, m.p.
183-185.degree. C.;
[0332] (1RS, 2SR,
3RS)-3-(2-Carboxymethoxy-4-ethyloxyphenyl)-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, m.p.
194-196.degree. C.
[0333] (1RS, 2SR, 3RS)-3-(2-Carboxyethylmethoxy-4-methoxyphenyl)-
1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid, m.p. 148-149.degree. C.;
[0334] (1RS, 2SR,
3RS)-3-[2-[(3-Carboxypyridin-2-yl)oxy]-4-methoxyphenyl]--
1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy) indane-2-carboxylic
acid m.p. 152-155.degree. C.
[0335] (1RS, 2SR,
3RS)-3-[2-[Carbo(N,N-diethylcarbamoyl)methoxy]methoxy-4--
methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carbo-
xylic acid, m.p. 181-182.degree. C.;
[0336] (1RS, 2SR,
3RS)-1-(3,4-Methylenedioxyphenyl)-3-[4methoxy-2-(2-prope-
n-1-yloxy)phenyl]-5-(prop-1-yloxy)indane-2-carboxylic acid, m.p.
168-170.degree. C.;
[0337] (1RS,
3RS)-3-[2-(3'-Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylen-
edioxyphenyl)-5-(prop-1-yloxy)indane dicyclohexylamine salt, m.p.
230-232.degree. C.;
[0338] (1RS, 2SR, 3SR)-
1,3,5-Tris(3,4-methylenedioxyphenyl)indane-2-carbo- xylic acid,
Anal. Calc. for C.sub.31H.sub.22O.sub.8.multidot.5/8 H.sub.2O: C,
69.76; H, 4.39. Found: C, 69.81, H, 4.46;
[0339] (1RS, 2SR,
3RS)-1-[2-(3-Hydroxyprop-1-yloxy)-4,5-methylenedioxyphen-
yl)-3-(4-methoxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
dicyclohexylamine salt, m.p. 165-167.degree. C.;
[0340] (1RS, 2SR,
3RS)-1-(2-Methoxy-4,5-methylenedioxyphenyl)-3-(4-methoxy-
phenyl)-5-(prop-1-yloxy)indane-2-carboxylate dicyclohexylamine
salt, m.p. 120-122.degree. C.;
[0341] (1RS, 2SR,
3RS)-5-Methoxy-1-(4-methoxy-2,3-methylenedioxyphenyl)-3--
(4-methoxyphenyl)indane-2-carboxylate dicyclohexylamine salt, m.p.
187-188.degree. C.;
[0342] (1RS, 2SR,
3RS)-5-(3-Buten-1-yloxy)-3-(4-methoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl)indane-2-carboxylic acid, m.p. 127-129.degree.
C.;
[0343] (1RS, 2SR,
3RS)-5-(But-1-yloxy)-3-(1-methoxyphenyl)-1-(3,4-methylen-
edioxyphenyl)indane-2-carboxylic acid, m.p. 157-158.degree. C.;
[0344] (1RS, 2RS,
3SR)-5-Hydroxy-1-(3,4-methylenedioxyphenyl)-3-(4-trifluo-
romethoxyphenyl)indane-2-carboxylic acid; m.p. 100-104.degree.
C.;
[0345] (1RS, 2SR,
3RS)-5-Hydroxy-1-(3-indolyl)-3-(4-methoxyphenyl)indane-2-
-carboxylic acid, m.p. 138-140.degree. C.;
[0346] (1RS, 2SR,
3SR)-5-Hydroxy-1-(5-indolyl)-3-(4-methoxyphenyl)indane-2-
-carboxylate dicyclohexylamine salt, m.p. 235-240.degree. C.;
[0347] (1RS, 2S R,
3SR)-3-(4-Methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-
-methylthioindane-2-carboxylic acid; Anal. Calc. for
C.sub.25H.sub.22O.sub.5.multidot.1/2 H.sub.2O: C, 67.70; H, 5.23.
Found: C, 67.60; H, 5.40;
[0348] (1RS, 2RS,
3SR)-5,6-(Methylenedioxy)-1-(3,4-methylenedioxyphenyl)-3-
-(4-trifluoromethoxyphenyl)indane-2-carboxylic acid, m.p.
170-172.degree. C.;
[0349] (1RS , 2SR,
3SR)-4-Benzyl-1,3-bis(4-methoxyphenyl)indane-2-carboxyl- ate,
dicyclohexylamine salt; m.p. 160-162.degree. C.;
[0350] (1RS, 2SR,
3SR)-4-Benzyl-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyp-
henyl)indane-2-carboxylate, dicyclohexylamine salt; m.p.
159-160.degree. C.;
[0351] Trans, Trans-1,3-Bis(4-methoxyphenyl)indane-2-carboxamide,
m.p. 223-225.degree. C.;
[0352] (1RS, 2SR,
3SR)-5-Benzyloxy-1,3-bis(3,4-methylenedioxyphenyl)indane- -2
carboxylic acid, m.p. 191-193.degree. C.;
[0353] (1RS, 2SR, 3SR)-3-[4-Methoxy-2-[2-(methylphosphinyl)
eth-1-yl]phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-ca-
rboxylate disodium salt; (exact mass) M.sup.++Na: 619.1462
(.DELTA.=-1.2 mDa for C.sub.30H.sub.31O.sub.8PNa.sub.3)
[0354] (1RS, 2SR, 3RS, 1RS,
SR)-3-[2-[1'-carboxyeth-1'-yloxy)-4-methoxyphe-
nyl]-1-(3,4-methylenedioxylphenyl)-5-(prop-1-yloxy)
indane-2-carboxylic acid
[0355] (1RS, 2SR,
3SR)-3-(4-Methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5--
methylsulfoxylindane-2-carboxylic acid;
EXAMPLE 121
(1RS, 2SR,
3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4--
methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate disodium
salt:
[0356] a) Methyl (1RS, 2SR,
3RS)-3-[2-[(4-Formylpyridin-3-yl)oxy]-4-methox-
yphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)
indane-2-carboxylate
[0357] To a solution of Methyl (1RS, 2SR,
3RS)-3-(2-hydroxy-4-methoxypheny-
l)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)
indane-2-carboxylate (300 mg, 0.63 mmol) in DMF (4 mL) was added
K.sub.2CO.sub.3 (109 mg, 0.79 mmol) and 3-fluoro-4-formylpyridine
(150 mg, 1.2 mmol). The reaction mixture was heated to reflux under
Argon for 2 h. After cooling to room temperature it was partitioned
between 3N HCl and ethyl acetate. The ethyl acetate extract was
washed with water, aqueous NaHCO.sub.3 and brine and dried
(Mg.sub.2SO.sub.4). The solvent was removed in vacuo. The residue
was purified by flash column chromatography (silica gel, gradient
elution from 10% to 20% ethyl acetate/hexanes) to afford the title
compound (128 mg, 42%).
[0358] b) Methyl (1RS, 2SR
3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methox-
yphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)
indane-2-carboxylate
[0359] To a solution of Methyl (1RS, 2SR,
3RS)-3-[2-[(4-formylpyridin-3-yl-
)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)
indane-2-carboxylate (128 mg, 0.24 mmol) in t-BuOH (10 mL) was
added a solution of NaCl.sub.2 (34 mg, 0.28 mmol) and
NH.sub.2SO.sub.3H (40 mg, 0.42 mmol) in water (6mL). The reaction
mixture was stirred at room temperature for 2 h and it was
partitioned between water and ethyl acetate. The ethyl acetate
extract was washed with water and brine and dried
(Mg.sub.2SO.sub.4). The solvent was removed in vacuo. The residue
was purified by flash column chromatography (silica gel, 25% ethyl
acetate/hexanes containing 5% of acetic acid) to afford the title
compound (90 mg, 69%).
[0360] c) (1RS, 2SR,
3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxypheny-
l]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)
indane-2-carboxylate disodium salt
[0361] To a solution of Methyl (1RS, 2SR,
3RS)-3-[2-[(4-Carboxypyridin-3-y-
l)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)
indane-2-carboxylate (90, 0.15 mmol) in isopropanol (2 mL) was
added 1M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was
heated to reflux for 12 h, then concentrated under reduced
pressure. The residue was partitioned between dilute HCl and ethyl
acetate. The ethyl acetate extract was washed with water and dried
(Mg.sub.2SO.sub.4). The solvent was removed in vacuao. The residue
was purified by flash column chromatography (silica gel, 30% ethyl
acetate/hexanes containing 5% of acetic acid) to afford the title
compound (65 mg, 74%); m.p. 220-222.degree. C. (dec.) (disodium
salt).
EXAMPLE 122
2.2-Dimethylpropanoyloxymethyl
(1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxy-
phenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate
sodium salt
[0362] a) 2.2-Dimethylpropanoyloxymethyl
(1RS,2SR,3RS)-3-(2-hydroxy-4-meth-
oxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxyl-
ate
[0363] (1RS, 2SR, 3RS
)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenediox-
yphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid potassium salt
(125 mg, 0.54 mmol) (obtained from the treatment of the
corresponding acid with KHCO.sub.3 (54 mg, 0.54 mmol)) was
dissolved in DMF (3 ml) and then pivaloyloxymethyl iodide (0.54
mmol) (prepared from pivaloyloxymethyl chloride (73 mg, 0.54 mmol)
and excess sodium iodide in acetone) was added. The reaction
mixture was stirred overnight and then partitioned between dil. HCl
and ethyl acetate. The organic layer was washed with water and
brine then dried (MgSO.sub.4 anhyd.) filtered and evaporated. The
product was purified by column chromatography to provide 122(a)
(120 mg, 77%) as a colorless oil.
[0364] b) 2,2-Dimethylpropanoyloxymethyl (1RS, 2SR,
3RS)-3-(2-benzyloxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxy-
phenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0365] 2,2-Dimethylpropanoyloxymethyl (1RS
,2SR,3RS)-3-(2-hydroxy-4-methox-
yphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylat-
e (280 mg, 0.5 mmol) in dry DMF (3 ml) was added to NaH (18 mg, 0.6
mmol) in a small volume of dry DMF. The mixture was stirred at RT
for 20 min. then benzyl bromoacetate (137 mg, 0.6 mmol) was added.
After stirring for 1.5 h the product was partitioned between 3M
aqueous HCl and ethyl acetate. The organic layer was washed with
water then brine, then dried MgSO.sub.4 anhyd.) filtered and
evaporated to give an oil. The product was purified by column
chromatography to provide 122 (b) (240 mg, 66%) as a colorless
oil.
[0366] c) 2.2-Dimethylpropanoyloxymethyl
(1RS,2SR,3RS)-3-(2-carboxymethoxy-
-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-c-
arboxylic acid.
[0367] 2,2-Dimethylpropanoyloxymethyl (1RS
,2SR,3RS)-3-(2-benzyloxycarbony-
lmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-in-
dane-2-carboxylate (240 mg, 0.3 mmol) was dissolved in a 2:1
mixture of ethyl acetate and ethanol (3 ml) and then 50 mg of Pd/C
was added. The mixture was stirred at room temperature under a
H.sub.2 atmosphere for 3 h. The catalyst was then filtered, the
solvent concentrated in vacuo and the resultant oil purified by
flash column chromatography. The title compound was obtained (180
mg, 86%) as a colorless oil.
[0368] MS (exact mass) (M+Na).sup.+: 647.2335 (sodium salt)
[0369] (D=-2.3. mDa for C.sub.33H.sub.38O.sub.11Na)
[0370] mp 190-195.degree. C. (dec, sodium salt)
EXAMPLE 123
(1S, 2R,
3S)-3-[2-[Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy)eth-1-ylo-
xymethoxyl-4-methoxyphenyl-1-(3,4-methlenedioxyphenyl)-5-prop-1-yloxy)inda-
ne-2-carboxylate sodium salt
[0371] a) Allyl (1S, 2R,
3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0372] (1S, 2R,
3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylened-
ioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (4.8 g, 9.5
mmol) was dissolved in dry acetonitrile (30 ml) and DBU (1.7 ml,
11.4 mmol) was added followed by allyl bromide (3,4 g, 28. mmol).
After stirring for 0.5 h. the product was partitioned between 3M
aqueous HCl and ethyl acetate. The organic layer was washed with
water and brine, then dried (MgSO.sub.4 anhyd.) filtered and
evaporated to give an oil. The product was purified by column
chromatography to provide the title compound as a pale yellow oil
(5.7 g, quantitative).
[0373] b) Allyl (1S, 2R,
3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylen-
edioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0374] Allyl (1S, 2R,
3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (1.7 g, 3.11
mmol) was dissolved in allyl alcohol (20 ml) and then 15 drops of
conc. HCl was added. The resulting solution was stirred at
65.degree. C. for 2 h. After removing the solvent the residue was
partitioned between water and ethyl acetate. The organic layers
were washed with water, 5% aqueous NaHCO.sub.3 and brine; then
dried (MgSO.sub.4 anhyd.), filtered and evaporated to give an oil.
The product was purified by column chromatography to provide the
title compound as a pale yellow oil (1.26 g, 81%).
[0375] c) Allyl (1S, 2R,
3S)-3-(2-Carbo-1-tert-butoxymethoxy-4-methoxyphen-
yl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0376] Allyl (1S, 2R,
3S)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedi-
oxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (1.0 g, 2 mmol) in
dry DMF (4 ml) was added to NaH (57 mg, 2.4 mmol) in a small volume
of dry DMF. The mixture was stirred at RT for 20 min., then
tert-butyl bromoacetate (974 mg, 5 mmol) was added. After stirring
for 0.5 h., the product was partitioned between 3M aqueous HCl and
ethyl acetate. The organic layer was washed with water, brine and
dried (MgSO.sub.4 anhyd.), filtered and evaporated to give an oil.
The product was purified by column chromatography to provide the
title compound (1.1 g, 93%) as a pale yellow oil.
[0377] d) Allyl (1S, 2R,
3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0378] Allyl (1S, 2R,
3S)-3-(2-carbo-tert-butoxymethoxy-4-methoxyphenyl)-1-
-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
(765 mg, 1.24 mmol) was dissolved in TFA (5 ml) containing a few
drops of anisole. The reaction mixture was stirred at RT for 20
min. The solvent was eliminated, the residue was diluted with ethyl
acetate, washed with water, brine and dried (MgSO.sub.4 anhyd.),
filtered and evaporated. The product was purified by column
chromatography to provide the title compound (575 mg, 83%) as a
colorless oil.
[0379] e) Allyl (1S, 2R,
3S)-3-[2-[Carbo-(1RS)-1-(2-methoxy-2-methylpropio-
nyloxy)eth-1-yloxymethoxy]-4-methoxyphenyl-1-(3,4-methlenedioxyphenyl)-5-p-
rop-1-yloxy)indane-2-carboxylic acid sodium salt
[0380] Allyl (1S, 2R,
3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (287 mg, 0.5
mmol) was dissolved in DMF (5 ml) and Cs.sub.2CO.sub.3 (333 mg, 1
mmol) added followed by (1S)-1-bromoethyl
2-methoxy-2-methylpropionate (225 mg, 1 mmol). The reaction mixture
was stirred at RT overnight, then partitioned between water and
ethyl acetate, washed with dil. HCl and brine, dried (MgSO.sub.4
anhyd.), filtered and evaporated to give an oil. The product was
purified by column chromatography to provide the title compound
(260 mg, 74 %) as a colorless oil.
[0381] f) (1S, 2R,
3S)-3-[2-Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxv)-
eth-1-yloxymethoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-prop-1-
-yloxy)indane-2-carboxylic acid sodium salt
[0382] Allyl
(1S,2R,3S)-3-[2-Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy-
eth-1-yloxymethoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop--
1-yloxy)indane-2-carboxylate (260 mg, 0.37 mmol) was dissolved in
CH.sub.2Cl.sub.2 (2 ml) and
tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.037 mmol) added
followed by tri-n-butyltin hydride (0.11 ml, 0.4 mol). The reaction
mixture was stirred at RT for 3 h then quenched with 3N HCl and
stirred for 20 min. The organic layer was diluted with ethyl
acetate washed with water then brine, dried (MgSO.sub.4 anhyd.),
filtered and evaporated to give an oil. The product was purified by
column chromatography to provide the title compound (210 mg, 85 %)
as a colorless oil.
[0383] MS (exact mass) (M+Na).sup.+: 687.2415 (sodium salt)
[0384] (D=+0.3. mDa for C.sub.36H.sub.40O.sub.12Na)
EXAMPLE 124
(1RS, 2SR,
3RS)-2-Amino-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)-indane
[0385] (1RS, 2SR,
3RS)-3-(2-tert--butoxycarbonylmethoxy-4-methoxyphenyl)-1-
-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18
mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in dry
benzene (4 ml) and heated at 40.degree. C. for 2 h and at
75.degree. C. for 2 h. The reaction mixture was then partitioned
between 1N HCl and ethyl acetate. The organic layer was washed with
water and brine, dried (MgSO.sub.4 anhyd.), filtered and evaporated
to give the corresponding isocianate as a colorless oil. After
purification by column chromatography (silica gel, ethyl
acetate/hexane 30:70), the isocianate (100 mg) thus obtained was
dissolved in 1M HCl in dioxane (3 mL) and the mixture was heated at
80.degree. C. overnight. The solvent was removed in vacuo, the
residue was partitioned between ethyl acetate and water. The
organic layer was washed with brine, dried (MgSO.sub.4) and
concentrated to give a colorless oil that was purified by HPLC (1:1
CNCH.sub.3:H2O(containing 0.1% TFA)) to produce the desired product
(40 mg, 42%) as an off-white solid, m.p. 181-182.degree. C.
(dec).
EXAMPLE 125
(1RS, 2SR, 3RS)-2-
Aminomethyl-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-
-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane
[0386] a) (1RS, 2SR,
3RS)-2-Hydroxymethyl-3-(2-tert-butoxycarbonylmethoxy--
4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
(1RS, 2SR,
3RS)-2-Hydroxymethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylened-
ioxyphenyl)-5-(prop-1-yloxy)indane (634 mg, 1.43 mmol) was
dissolved in dry acetone (15 ml) then K.sub.2CO.sub.3 (1.97 g, 14.3
mmol) and tert-butyl bromoacetate (416 mg, 2.14 mmol) was added.
The reaction mixture was stirred overnight. The solvent was then
eliminated the residue partitioned between water and ethyl acetate.
The organic layer was washed with dilute HCl, water, brine and
dried (MgSO.sub.4 anhyd.) filtered and evaporated to give an oil.
The product was purified by column chromatography to provide 125(a)
(792 g, 98%) as a pale yellow oil.
[0387] b) (1RS, 2SR,
3RS)-2-Azidomethyl-3-(2-tert-butoxycarbonylmethoxy-4--
methoxyphenyl)- 1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
(1RS, 2SR,
3RS)-2-Hydroxymethyl-3-(2-2-tert-butoxycarbonylmethoxy-4-methoxyphen-
yl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (792 mg,
1.41 mmol) was dissolved in CH.sub.2Cl.sub.2 (10 ml) cooled at
0.degree. C., triethylamine (485 mg, 4.8 mmol) and methanesulfonyl
chloride (229 mg, 2 mmol) were then added. The reaction mixture was
kept at 0.degree. C. for 0.5 h and then partitioned between water
and ethyl acetate. The organic layer was washed with dilute HCl,
water, brine and dried (MgSO.sub.4 anhyd.) filtered and evaporated
to produce the desired mesylate (680 mg, 78%). Without further
purification, the mesylate was dissolved in dry DMF (5 ml), and
NaN.sub.3 was added. The reaction mixture was stirred overnight at
60.degree. C. and, after cooling to RT, it was partitioned between
water and ethyl acetate. The organic layer was washed with dilute
HCl, water, brine and dried (MgSO.sub.4 anhyd.) filtered and
evaporated. The residue was purified by column chromatography to
produce the desired azide as a colorless oil (484 mg, 75%).
[0388] c) 1RS, 2SR,
3RS)-2-Aminomethyl-3-(2-tert-butoxycarbonylmethoxy-4-m-
ethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
(1RS, 2SR,
3RS)-2-Azidomethyl-3-(2-2-tert-butoxycarbonylmethoxy4-methoxyphenyl)
1 - (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (484 mg, 0.78
mmol) was dissolved in ethanol (12 ml) and ethyl acetate (3 ml) and
then 80 mg of 10% Pd/C were added. The reaction mixture was stirred
under H.sub.2 atmosphere for 4 h. The catalyst was filtered, the
solvent eliminated and the residue purified by column
chromatography (ethyl acetate/hexane 25/75 followed by methanol) to
obtained the desired amine (320 mg, 66%) as a colorless oil.
[0389] d) (1RS, 2SR,
3RS)-2-Aminomethyl-3-(2-carboxymethoxy-4-methoxyphyl)-
-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
[0390] (1RS, 2SR,
3RS)-2-Aminomethyl-3-(2-2-tert-butoxycarbonylmethoxy4-me-
thoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
(765 mg, 1.24 mmol) was dissolved in TFA (5 ml) containing a few
drops of anisole. The reaction mixture was stirred at RT for 20
min. The solvent was eliminated the residue was diluted with ethyl
acetate washed with water, brine and dried (MgSO.sub.4 anhyd.),
filtered and evaporated. The product was purified by column
chromatography to provide the title compound (575 mg, 83%) as a
white powder m.p. 237-242.degree. C.
EXAMPLES 126-153
Indan-5-yl-(1RS, 2SR,
3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-met-
hylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid sodium
salt, m.p. 181-183.degree. C. dec.
[0391] 3.5-Dimethoxyphenyl-(1RS, 2SR, 3RS
)-3-(2-carboxymethoxy-4-methoxyp-
henyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate
acid sodium salt m.p. 185-189.degree. C. dec.
[0392] (1RS)-1-(2-Methoxy-2-methylpropionyloxy)eth-1-yl (1RS, 2SR,
3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5--
(prop-1-yloxy)indane-2-carboxylate sodium salt m.p. 178-181.degree.
C. dec.
[0393] N,N-Dimethylcarbamoylmethyl (1RS, 2SR,
3RS)-3-(2-carboxymethoxy-4-m-
ethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-loxy)indane-2-carboxy-
late sodium salt
[0394] m.p. 170-174.degree. C. dec.
[0395] Ethoxycarboxyloxymethyl (1RS, 2SR,
3RS)-3-(2-carboxymethoxy-4-metho-
xyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylat-
e sodium salt MS (exact mass) (M+Na).sup.+: 645.1959 (sodium salt)
(D=-1.1 mDa for C.sub.33H.sub.34O.sub.12Na)
[0396] Benzoyloxymethyl (1RS, 2SR,
3RS)-3-(2-carboxymethoxy-4-methoxypheny-
l)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
sodium salt
[0397] MS m/e 672 (M+NH.sub.4).sup.+
[0398] Cyclohexyloxycarboxyloxymethyl (1RS, 2SR,
3RS)-3-(2-carboxymethoxy--
4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-car-
boxylate sodium salt
[0399] MS (exact mass) (M+Na).sup.+: 699.2453 (sodium salt)
(D=-3.5. mDa for C.sub.37H.sub.40O.sub.12Na)
[0400] Ethyl (1RS, 2SR,
3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-m-
ethylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium
salt
[0401] MS (exact mass) M.sup.+: 548.2040 (free acid)
[0402] (D=+0.6. mDa for C.sub.31H.sub.32O.sub.9)
[0403] (1S, 2R,
3S)-3-[(2-Carboxy-(2',6'-dimethylphenyl)methoxyl-4-methoxy-
phenyl]-1(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
sodium
[0404] MS (exact mass) (M+Na).sup.+: 647.2264 (sodium salt)
[0405] D=-0.7. mDa for C.sub.37H.sub.36O.sub.9Na)
[0406] (1S, 2R,
3S)-3-[[(2-Carboxycyclopentylmethoxy)-4-methoxyphenyl]-1-(-
3,4-methylenedioxyphenyl-5-(prop-1-yloxy)indane-2-carboxylate
sodium salt
[0407] MS (exact mass) (M+Na).sup.+: 611.2282 (sodium salt)
[0408] (D=-2.5. mDa for C.sub.34H.sub.36O.sub.9Na)
[0409] (1S, 2R,
3S)-3-[2-[Carbo(indan-5-yloxy)methoxy]-4-methoxyphenyl]-1--
(3,4-methylenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylic acid
sodium salt
[0410] MS (exact mass) (M+Na).sup.+: 659.2281 (sodium salt)
[0411] (D=-2.4. mDa for C.sub.38H.sub.36O.sub.9Na)
[0412] (1S, 2R,
3S)-3-[2-Carbo(eth-1-yloxy)methoxyl-4-methoxyphenyl]-1-(3,-
4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
sodium salt
[0413] MS (exact mass) (M+2Na-H).sup.+: 593.1769 (sodium salt)
[0414] (D=-0.6 mDa for C.sub.31H.sub.31O.sub.9Na.sub.2)
[0415] (1RS, 2SR,
3RS)-3-(2-Carboxyethylmethoxy-4-methoxyphenyl)-1-(3,4-me-
thylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0416] m.p. 148-149.degree. C.
[0417] (1RS, 2SR, 3RS)-3-[2-[2-[2-
Diethylamino)-2-oxoethoxy]-2-oxoethoxy]-
-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-ca-
rboxylic acid
[0418] m.p. 181-182.degree. C.
[0419] (1RS, 2SR,
3RS)-2-Trifluoromethylsulfonamidomethyl-3-(2-carboxymeth-
oxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
[0420] m.p. 184-186.degree. C.
[0421] (1RS, 2SR,
3RS)-2-Aminoethyl-3-(2-carboxymethoxy-4-methoxyphenyl)-1-
-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
[0422] m.p. 207-211.degree. C.
[0423] Indan-5-yl (1S, 2R,
3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-
-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium
salt
[0424] Cyclopentyl (1S, 2R,
3S)-3-2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-
-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium
salt.
[0425] Ethoxycarboxymethyl (1S, 2R,
3S)-3-(2-carboxymethoxy-4-methoxypheny-
l)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
sodium salt.
[0426] (1RS)-1-(1-Methylethoxycarboxy)eth-1-yl (1RS, 2SR,
3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5--
(prop-1-yloxy)indane-2-carboxylate sodium salt.
[0427] m.p 151-155.degree. C.
[0428] Ethyl (1S, 2R,
3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
(1S, 2R,
3S)-3-[2-Carbomethoxymethoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyph-
enyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
[0429] (1S, 2R,
3S)-3-[2-Carbobenzoyloxymethoxymethoxyl-4-methoxyphenyl]-1-
-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid sodium
[0430] (1S, 2R,
3S)-3-[2-(Carboethoxycarboxyloxymethoxymethoxy)-4-methoxyp-
henyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid sodium salt
[0431] (1S, 2R,
3S)-3-[2-(Carboacetoxymethoxymethoxy)-4-methoxyphenyl]-1-(-
3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
sodium salt
[0432] (1S, 2R,
3S)-3-[2-[Carbophthalidylmethoxy)-4-methoxyphenyl]-1-(3,4--
methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
sodium salt
[0433] (1S, 2R,
3S)-3-[2-Carbo-(2-methoxy-2-methylpropionyloxymethoxymetho-
xyl-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-
-carboxylic acid sodium salt
EXAMPLE 153
[0434] (1S,2R,3S
)-3-[2-Carbo-(2,2-dimethylpropanoyloxymethoxymethoxyl-4-m-
ethoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carbox-
ylic acid sodium salt
[0435] To a solution of (1S, 2R,
3S)-3-[2-Carboxymethoxy-4-methoxyphenyl]--
1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid monopotassium salt (170 mg, 0.3 mmol) (obtained by treatment
of the corresponding diacid (156 mg, 0.3 mmol) with 1 equiv. of
KHCO.sub.3 (30 mg, 0.3 mmol)) in DMF (4 mL) pivaloyloxymethyl
iodide (74 mg, 0.3 mmol) was added. The reaction mixture was
stirred at RT for 0.5 h and more pivaloyloxymethyl iodide was then
added (20 mg. 0.08 mmol) and then stirred for an additional 0.5 h.
The reaction mixture was partitioned between dilute aqueous HCl and
ethyl acetate. The ethyl acetate extract was washed with water and
brine and dried (MgSO.sub.4 anhydrous). The solvent was removed in
vacuo and the residue was purified by flash column chromatography
(silica gel, Ethyl Acetate/hexane/HOAc 30/65/5) to obtain the
desired compound as a white foam (140 mg, 73%) as the free acid
which was converted to its sodium salt. m.p. 128-133.degree. C. MS
(exact mass) M.sup.++Na: 679.2116 (sodium salt) (D=+1.2 mDa for
C.sub.35H.sub.37O.sub.11Na.sub.2)
EXAMPLE 154
(1RS, 2SR,
3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methtlenedioxy-
phenyl)-5-(prop-1-yloxy)indan-2-yl acetic acid
[0436] a) (1RS, 2SR,
3RS)-3-(4-Methoxy-2-methoxymethoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid. A
solution of methyl (1RS, 2RS,
3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methyl-
enedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (2.42 g, 4.6
mmol) in isopropyl alcohol (30 ml) with aqueous NaOH (8 ml of 5 N
solution) was refluxed for 4 h. The resultant mixture was
partitioned between EtOAc and 3N HCl. The organic extract was
washed with H.sub.2O then brine, dried (Na.sub.2SO.sub.4) and
solvent removed in vacuo to afford the title compound as a
colorless oil (1.98 g, 84%).
[0437] b) Methyl (1RS, 2SR,
3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3-
,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. To a
solution of(1RS, 2SR,
3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-me-
thylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (1.98
g, 3.91 mmol) in acetonitrile (15 ml) was added DBU (0.655 g, 4.3
mmol) followed by iodomethane (2.77 g, 19.5 mmol). The reaction
mixture was stirred at room temperature 3.5 h then partitioned
between EtOAc and 3N HCl. The organic extract was washed with
H.sub.2O, saturated NaHCO.sub.3 solution, H.sub.2O, then brine,
dried (Na.sub.2SO.sub.4) and solvent removed in vacua to provide
the title compound (1.79 g, 88%) as an oil.
[0438] c) (1RS, 2RS,
3RS)-2-Hydroxymethyl-3-(4-methoxy-2-methoxymethoxyphe-
nyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a
solution of methyl (1RS, 2SR,
3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methyl-
enedioxyphenyl) -5-(prop-1-yloxy)indane-2-carboxylate (4.45 g, 8.5
mmol) in THF (35 ml) stirred at 0.degree. C. was added lithium
aluminum hydride (17 ml of a 1M solution in THF). The cooling bath
was removed and stirring continued for 18 h. The reaction was
quenched by addition of saturated aqueous ammonium chloride
solution then partitioned between EtOAc and 3N HCl. The organic
extract was washed with H.sub.2O, saturated NaHCO.sub.3 solution,
H.sub.2O, then brine, dried (Na.sub.2SO.sub.4) and solvent removed
in vacuo to afford the tide compound as an oil (4.13 g, 98%).
[0439] d) (1RS, 2RS,
3RS)-2-Methanesulfonyloxymethyl-3-(4-methoxy-2-methox-
ymethoxyphenyl)-1-(3,4-methlenedioxyphenyl)-5-(prop-1-yloxy)indane.
To a solution of (1RS, 2RS,
3RS)-2-hydroxymethyl-3-(4-methoxy-2-methoxymethoxy- phenyl)-1-(3
,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (1.388 g, 2.82
mmol) in methylene chloride (10 ml) with TEA (1.2 ml) stirred under
argon at 0.degree. C. was added methanesulfonyl chloride (0.41 g,
3.5mmol). The cooling bath was removed and stirring continued for 1
h. The mixture was partitioned between EtOAc and 3N HCl. The
organic extract was washed with H.sub.2O, saturated NaHCO.sub.3
solution, H.sub.2O, then brine, dried (Na.sub.2SO.sub.4) and
solvent removed in vacuo to afford the title compound as an oil
(1.52 g, 95%).
[0440] e) 1RS, 2RS,
3RS)-2-Cyanomethyl-3-(4-methoxy-2-methoxymethoxyphenyl-
)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane. (1RS, 2RS,
3RS)-2-Methanesulfonyloxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3-
,4-methylenedioxyphenyl)-5-(prop-1-yloxy) indane (1.5 g, 2.96 mmol)
was stirred in DMF (10 ml) under argon with NaCN (1.45 g, 29.6
mmol) at 60.degree. C. for 20 h then cooled and partitioned between
EtOAc and 3N HCl. The organic extract was washed with H.sub.2O,
saturated NaHCO.sub.3 solution, H.sub.2O, then brine, dried
(Na.sub.2SO.sub.4) and solvent removed in vacuo to afford the title
compound as an oil (1.27 g, 86%).
[0441] f) 1RS, 2RS,
3RS)-2-Cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,-
4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane. 1RS, 2RS,
3RS)-2-Cyanomethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylened-
ioxyphenyl)-5-(prop-1-yloxy) indane (300 mg, 0.60 mmol) was
dissolved in EtOH (4 ml) with concentrated HCl (0.1 ml) then
refluxed for 1 h. the mixture was cooled then partitioned between
EtOAc and 3N HCl. The organic extract was washed with H.sub.2O,
saturated NaHCO.sub.3 solution, H.sub.2O, then brine, dried
(Na.sub.2SO.sub.4) and solvent removed in vacuo to afford the title
compound as a solid foam (250 mg, 91%).
[0442] g) 1RS, 2RS,
3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cya-
nomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a
solution of 1RS, 2RS,
3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1--
(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (250 mg, 0.55
mmol) in DMF (4 ml) stirred at 0.degree. C. under argon added NaH
(21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at
0.degree. C. for 15 min then t-butylbromoacetate (107 mg, 0.55
mmol) was added. The cooling bath was removed and the mixture was
stirred for 3 h at room temperature then partitioned between EtOAc
and 3N HCl. The organic extract was washed with H.sub.2O, saturated
NaHCO.sub.3 solution, H.sub.2O, then brine, dried
(Na.sub.2SO.sub.4) and solvent removed in vacuo. The residue was
purified by flash chromatography on silica gel, (eluent 25-50%
Et.sub.2O/hexanes) to afford the title compound as an oil (247 mg,
79%).
[0443] h) 1RS, 2RS,
3RS)-1-(2-Carboxymethoxy-4-methoxyphenyl)-2-cyanomethy-
l-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane. 1RS, 2RS,
3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-met-
hylenedioxyphenyl)-5-propoxyindane (240 mg, 0.42 mmol) was stirred
in methylene chloride (3 ml) with TFA (0.8 ml) under argon at room
temperature for 1 h then partitioned between EtOAc and 3N HCl. The
organic extract was washed with H.sub.2O then brine, dried
(Na.sub.2SO.sub.4) and solvent removed in vacuo to afford the
product as an oil (190 mg, 88%).
[0444] i) (1RS, 2SR,
3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-meth-
ylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-ylacetic acid. To a
solution of 1RS, 2RS,
3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4--
methylenedioxyphenyl)-5-(prop-1-yloxy)indane (290 mg, 0.56 mmol) in
methanol (ca. 1 ml) was added aqueous 2 N NaOH solution (0.3 ml)
followed by H.sub.2O (8 ml) then (with caution) Na.sub.2O.sub.2
(120 mg). The mixture was heated to 70.degree. C. and stirred for
20 h at which time HPLC showed only 15% hydrolysis. The mixture was
stirred at 85.degree. C. for 3 days with 3 (100 mg) portions of
Na.sub.2O.sub.2 added each day, the reaction mixture was
partitioned between EtOAc and 3N HCl. The organic extract was
washed with H.sub.2O then brine, dried (Na.sub.2SO.sub.4) and
solvent removed in vacuo to afford the product as an oil (228 mg,
90% pure by HPLC) Final purification was obtained by
crystallization as the bis cyclohexylamine salt. mp 210-212.degree.
C.
EXAMPLE 155
[0445] Following the procedure outlined on Example 154 the
following compound was made:
(1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(-
3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-yl-acetic acid.
m.p. 139-146.degree.
EXAMPLE 156
[0446] 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.
[0447] Inhalant Formulation
[0448] A compound of Formula 1, (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
[0449] Procedure for tablets
[0450] Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a
suitable mixer/blender.
[0451] 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.
[0452] 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.
[0453] Step 4 The wet granules are then dried in an oven at
140.degree. F. (60.degree. C.) until dry.
[0454] Step 5 The dry granules are lubricated with ingredient No.
5.
[0455] Step 6 The lubricated granules are compressed on a suitable
tablet press.
[0456] Parenteral Formulation
[0457] 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.
* * * * *