AP433A - Endothelin receptor antagonistis. - Google Patents

Abstract

Novel indane and indene derivatives are described which are endothelin receptor antagonists.

Description

ENDQTHELIN RECEPTOR ANTAGONISTS

FIELD OF INVENTION

The present invention relates to novel indane and indene derivatives, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists.

BACKGROUND

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. Of these, only ET-1 and ET-3 have been found to be expressed in mammalian systems. [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

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-ί-

myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.

In vivo, endothelin has pronounced effects on 5 blood pressure and cardiac output. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in rats causes a transient, dose-related depressor response (lasting 0.5 to 2 minutes) followed by a sustained, dose-dependent rise in arterial blood pressure which can remain elevated for 2 to 3 hours following dosing. Doses above 3 nmol/kg in a rat often prove fatal.

Endothelin appears to produce a preferential effect in the renal vascular bed. It produces a marked, long-lasting decrease in renal blood flow, accompanied by a significant decrease in GFR, urine volume, urinary sodium and potassium excretion. Endothelin produces a sustained antinatriuretic effect, despite significant elevations in atrial natriuretic peptide. Endothelin also stimulates plasma renin activity. These findings suggest that ET is involved in the regulation of renal function and is involved in a variety of renal disorders including acute renal failure, cyclosporine nephrotoxicity and chronic renal failure.

Studies have shown that in vivo, the cerebral vasculature is highly sensitive to both the vasodilator and vasoconstrictor effects of endothelin. Therefore,

ET may be an important mediator of cerebral vasospasm, a frequent and often fatal consequence of subarachnoid hemorrhage.

ET also exhibits direct central nervous system effects such as severe apnea and ischemic lesions which suggests that ET may contribute to the development of cerebral infarcts and neuronal death.

ET has also been implicated in myocardial ischemia (Nichols et al. Br. J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Circ. Res., 65: 1193-1200, 1989)

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-3coronary vasospasm (Fukuda et al., Eur. J. Pharm. 165: 301-304, 1989 and Luscher, Circ. 83: 701, 1991) heart failure, proliferation of vascular smooth muscle cells, (Takagi, Biochem & Biophys. Res. Commun.: 168: 537-543,

1990, Bobek gt al./ Am. J. Physiol. 258:408-C415, 1990) and atherosclerosis, (Nakaki et al., Biochem. & Biophys. Ras. Commun. 158: 880-881, 1989, and Lerman et al._f New Eng. J. of Med. 325: 997-1001, 1991). Increased levels of endothelin have been shown after coronary balloon angioplasty (Kadel et al.. No. 2491 Circ. 82: 627,

1990) .

Further, endothelin has been found to be a potent constrictor of isolated mammalian airway tissue including 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 has been associated with the induction of haemorrhagic and necrotic damage in the gastric mucosa (Whittle et al., Br. J. Pharm. 95: 10111013, 1988); Raynaud's phenomenon, Cinniniello et al._r Lancet 337: 114-115, 1991); Migraine (Edmeads, Headache, Feb. 1991 p 127); Sepsis (Weitzberg et al., Circ. Shock 33: 222-227, 1991; Pittet et al.. Ann. Surg. 213: 26225 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 (Biochejn, Biophys. Res. Commun.. 161: 1220-1227, 1989, Acta Physiol, Scand. 137:

317-318, 1989) .

Thus, endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, renal failure, cerebrovascular disease, myocardial ischemia, angina, heart failure, asthma, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin induced

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-4multiple organ failure or disseminated intravascular coagulation, cyclosporin-induced renal failure and as an adjunct in angioplasty and prevention of restenosis.

SUMMARY OF THE INVENTION

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 and atherosclerosis.

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 QF THE INVENTION

The compounds of this invention are represented by structural Formula (I) :

z.

(I)

wherein:

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-5Ri is -X(CH₂)_nAr or -X(CH₂)_nR₈ or

R₂ is hydrogen, Ar or (c);

Ρχ is -X(CH₂)_nR₈;

P₂ is -X(CH₂)_nRg, or -XRgY;

( R₃ and R5 are independently hydrogen, Rn, OH,

C!_₈alkoxy, S(O)_qR_11# N(Rg)₂, Br, F, I, Cl, CF₃, NHCORg, -RllCO₂R7, -XR9-Y or -X(CH₂)_nR₈ wherein the methylene groups of -X(CH₂)_nR₈ may be unsubstituted or substituted by one or more -(CH₂)_nAr groups;

R4 is hydrogen, Rn, OH, Ci_5alkoxy,

S (O)qRn,N(Rg)₂, -X(R_n), Br, F, I, Cl or NHCORg wherein the Ci_5alkoxy may be unsubstituted or substituted by

OH, methoxy or halogen;

Rg is independently hydrogen or Ci_4alkyl;

R7 is independently hydrogen, Ci_galkyl or f (CH₂)_nAr;

R₈ is hydrogen, R^, CO₂R7, PO₃H₂, P (0) (OH)R7, 25 CN, -C(O)N(Rg)₂, tetrazole or ORg;

Rg is Ci_io_aikyl» C₂_iQalkenyl or phenyl all of which may be unsubstituted or substituted by one or more OH, N(Rg)₂, COOH, halogen or XCi_5alkyl;

Rig is R₃ or R4;

Rn is Ci_₈alkyl, C₂_₈alkenyl, C₂_₈alkynyl all of which may be unsubstituted or substituted by one or more OH, CH₂OH, N(Rg)₂ or halogen;

X is (CH₂)_n, O, NRg or S(O)_q;

Y is CH₃ or X(CH₂)_nAr;

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Naphthyl, indolyl, pyridyl or 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 R3 or R4 groups;

A is C=0, or [C(R6)2J_m;

B is -CH2~ or -0-;

Z]_ and Z2 are independently hydrogen, C^_ galkyl, C2-ealkenyl, C2-galkynyl, OH, Cj-galkoxy,

S(0)qCx-galkyl, N(Rg)₂, Br, F, I, Cl, NHCORg,

-X(CH2)_n ^R8» phenyl, benzyl or C3_gcycloalkyl wherein the Ci-galkyl, C2-Qalkenyl or C2-8alkynyl may be optionally substituted by COOH, OH, CO(CH₂)_nCH₃, CO(CH₂)_nCH₂N(Rg)₂, or halogen; or Z]_ and Z2 together may be -0-A-0- on contiguous carbons;

Z3 is Zi or XR9Y;

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 • R2 is not hydrogen when X is S(O)q;

• when the optional double bond is present there is only one Rjq and there is no Pj;

’ the compound of Formula I is not (IRS)-1,3diphenylindene-2-carboxylic acid; (cis,cis)BAD ORIGINAL

0 π 4 3 3

-7(1RS,3SR)-1,3-diphenylindane-2-carboxylic acid; (IRS)-3-[3-Methyl-l-phenyl-(1H)-ind-2-en-l-yl] propionic acid; or (IRS)-2[1,3-diphenyl-(1H)ind-2-en-2-yl]ethanoic acid.

Also included in the invention are pharmaceutically acceptable salt complexes.

All alkyl, alkenyl, alkynyl and alkoxy 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 perhalogenation.

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.

Preferred compounds are those wherein Rj is X(CH₂)_nAr, (Ar is (a) or (b)), dihydrobenzofuranyl, benzodioxanyl, cyclohexyl, Cx_₄alkyl; R₂ is (a), (b) Οχ_ ₄alkyl, indolyl or hydrogen; R3 and R5 are independently hydrogen, OH, Cx_5alkoxy, halogen, -OCx_₄alkyl phenyl, ^R11^CO2^R7, C₁_₄alkyl, N(R₆)₂, NH(CO)CH₃, -X(CH₂)_nR_8/ -XRg pyridyl, phenyl or S(0)pCx-salkyl; R₄ is hydrogen, OH, Ci_5alkoxy, halogen, Ci_₄alkyl, N(Rg)₂, NH(CO)CH₃ or S(0)pCi_5alkyl; Ζχ, Z₂ and Z₃ are independently XR9Y, benzyl, hydrogen, OH, Cj-salkoxy, -N(R₈)₂, S(O)qCx_ galkyl, NHCORg, X(CH₂)_nRg or halogen, or Ζχ and Z₂ together may be -0-A-0 on contiguous carbons; Ρχ and P₂ are independently hydrogen, CO₂H or tetrazole; Ar is (a), (b), phenyl, or pyridyl; X is (CH₂)_n or oxygen.

More preferred are compounds wherein R₃ is hydrogen or -X(CH₂)_nR_8i RnC0₂ ^R7' R₄ and R5 are independently hydrogen, OH, Cx_5alkoxy, SCx-salkyl, F,

Br, Ci_₃alkyl or NH₂; Ζχ and Z₃ are hydrogen and Z₂ is hydrogen, OH, Cx_5alkoxy, halogen, X(CH₂)_nRg, NH₂, benzyl, NH(CO)CH₃, or Ζχ and Z₂ together may be 0-A-0.

r ίο

C r

< 25

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-8Most preferred are compounds wherein is (b) and R₂ is (a) or (b); A is CH₂, B is -O-; there is no optional double bond; Rj and XR₂ are trans to P^; Z₂ is OH, Cj_5alkoxy, -OCH₂CHCH₂ or hydrogen, Zj is hydrogen; R3 is hydrogen, X(CH₂)qCOOH or CH=CHCO₂H, R₄ is hydrogen, substituted phenyl, or Ci_₂alkoxy; and R5, R^q and P₂ are hydrogen.

Especially preferred are the following compounds:

(IRS, 2SR, 3SR)-1-(4-Methoxyphenyl)-3-(3, 4-methylenedioxyphenyl)indane-2-carboxylic acid;

(IRS, 2RS, 3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)indane-2-carboxylic acid;

(IRS, 2RS, 3SR)-5-Methoxy-3-(4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)indane-2-carboxylic acid;

(IRS, 2SR, 3SR)-1,3-Bis(3,4-methylenedioxyphenyl)-55-hydroxyindane-2-carboxylic acid;

(IRS, 2SR,3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-ΙΟ, 4-methylenedioxyphenyl)-5-(prop-l-yloxy)-indane-2carboxylic acid (IRS, 2SR, 3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1(2-methoxy-4,5-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid (IRS, 2SR, 3RS)-3-[2-(l-Carboxyeth-2-yloxy)-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid, bis-dicyclohexylamine salt;

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-9(1RS, 2SR, 3SR)-3-[2-[(E)-2-Carboxyethen-l-yl]-4methoxyphenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-1yloxy)indane-2-carboxylic acid;

(IRS, 2SR, 3SR)-3-[2-(2-Carboxyeth-l-yl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-l-yloxy) indane-2-carboxylic acid;

(IRS, 2SR,3RS)-3-[2- (3-Carboxyphenyl)-4-methoxyphenyl]-1(3, 4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2carboxylic acid

The present invention provides compounds of

Formula (I) above

R₂ which can be prepared by a process which comprises: a) reacting a compound of Formula (2) wherein

X is Ci_5alkyl

with a substituted benzaldehyde or aldehyde of Formula (3).

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- 10D-CHO (3) 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).

Cyclization of compound (4) in the presence of a suitable Lewis acid such as titanium tetracholoride or aluminum chloride or alternatively when Zj is 3-OR (meta)(where R is C^-salkyl, or benzyl), trifluoroacetic acid, provides an indanone of the Formula (5).

Dehydrogenation with 2,3-dichloro-5,6-dicyano1.4- 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).

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- 11 wherein

Alternatively, a compound of Formula Z2 and Z3 are hydrogen and

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°C followed by the addition of an acid chloride of formula (7):

provides a compound of formula (8):

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

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- 12magnesium malonate in a solvent such as ether to give a compound of formula (9):

Reaction of a compound of type (9) at reflux with 5% aqueous sodium carbonate gives compounds of formula (10):

r ('

wherein Ζχ, Z₂, Z3 and R^ are as defined for formula I or a group convertable to them, with an organomagnesium compound of Formula (12) wherein R₂ is defined for

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- 13(12)

R₂ (CH₂)_nMgBr

Formula I or a group convertable to it, in a suitable solvent at 0°C provides compounds of formula (13):

(13)

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^eC affords racemic compounds of formula (14).

Conjugate addition of nucleophiles to an ester derived from formula (14), followed by saponification affords compounds of formula (I) having an R^q 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^q substituent is hydrogen.

Reduction of compounds of formula (13) with triethylsilane and boron trifuoride etherate in a suitable solvent such as dichloromethane at 0°C followed by hydrogenation with hydrogen gas under pressure at_

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- 14approximately 60 psi in the presence of a suitable catalyst such as 10% palladium on charcoal affords compounds of formula (15) :

(15)

Alkylation or acylation of the ester enolate derived from formula (15) affords compounds wherein Ρχ and P₂ are as defined in formula (1).

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 15% 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) :

wherein Ζχ, Z₂ and Z3 are hydrogen; = R₂; 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°C followed by reaction with samarium II iodide in a suitable

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- 15solvent such as tetrahydrofuran and then saponification, provides compounds of formula (17)

COjH (17) r⁴

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.

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.

Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sublingually, transdermally, rectally, via inhalation or via buccal administration.

Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium

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- 16 stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose.

Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.

Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (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.

Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a

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ΑΡ000433

- 17single dose.

Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).

The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.

The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.

No unacceptable toxicological effects are expected when compounds of the invention are administered in, accordance with the present invention.

The biological activity of the compounds of Formula (I) are demonstrated by the following tests:

I. Binding Assay

A) Membrane Preparation

Rat cerebellum or kidney cortex were rapidly dissected and frozen immediately in liquid nitrogen or used fresh. The tissues, 1-2 g for cerebellum or 3-5 g for kidney cortex, were homogenized in 15 mis of buffer cont a in ing 2 OmM Tris HC1 and 5mM EDTA, pH 7.5 at 4 °C_

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-18using a motor-driven homogenizer. The homogenates were filtered through cheesecloth and centrifuged at 20,000 x g for 10 minutes at 4 °C. The supernatant was removed and centrifuged at 40,000 xg for 30 minutes at 4°C. The resulting pellet was resuspended in a small volume of buffer containing 50 mM Tris, 10 mM MgCl₂, pH 7.5; aliquotted with small vials and frozen in liquid nitrogen. The membranes were diluted to give 1 and 5 mg of protein for each tube for cerebellum and kidney cortex in the binding assay.

Freshly isolated rat mesenteric artery and collateral vascular bed were washed in ice cold saline (on ice) and lymph nodes were removed from along the major vessel. Then, the tissue was homogenized using a polytron in buffer containing 20 mM Tris and 5mM EDTA, pH 7.5 at 4°C in 15 ml volume for -6 gm of mesenteric artery bed. The homogenate was strained through cheesecloth and centrifuged at 2,000 xg for 10 min. at 4°C. The supernatant was removed and centrifuged at

40,000 xg for 30 min. at 4°C. The resulting pellet was resuspended as explained above for cerebellum and kidney cortex. Approximately 10 mg of membrane protein was used for each tube in binding experiments.

B) [¹²⁵1 ] El-zl Binding Protocol (¹²^I]ET-1 binding to membranes from rat cerebellum (2-5,mg protein/assay tube) or kidney cortex (3-8 mg protein/assay tube) were measured after 60 minutes incubation at 30°C in 50 mM Tris HC1, 10 mM MgCl₂, 0.05% BSA, pH 7.5 buffer in a total volume of 100 ml. Membrane protein was added to tubes containing either buffer or indicated concentration of compounds. [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 bad original 5

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- 193.0 ml cold buffer containing 50 mM Tris and 10 mM MgCl₂, 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%. ICsq’s for the compounds of this invention range from 0.1 nm to 50 gm.

II. In Vitro Vascular-Smooth Muscle Activity

Rat aorta are cleaned of connective tissue and adherent fat, and cut into ring segments approximately 3 to 4 mm in length. Vascular rings are suspended in organ bath chambers (10 ml) containing Krebs-bicarbonate solution of the following composition (millimolar):

NaCl, 112.0; KC1, 4.7; KH₂PO₄, 1.2; MgSO₄, 1.2; CaCl₂, 2.5; NaHCC>3, 25.0; and dextrose, 11.0. Tissue bath solutions are maintained at 37°C and aerated continuously with 95% 0₂/ 5% CO₂. 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.

ET-1 induced vascular contractions are expressed as a percentage of the response elicited by 60 mM KC1 for each individual tissue which is determined at

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-20the beginning of each experiment. Data are expressed as the mean ± S.E.M. Dissociation constants (Kj-,) of competitive antagonists were determined by the standard method of Arunlakshana and Schild. The potency range for compounds of this invention range from 0.1 nM to 50 gm.

The following examples are illustrative and are not limiting of the compounds of this invention.

EXAMPLE..1 (IRS.2RS,3SR)-1-(4-Methoxyphenyl)-3-phenylindaneacid

a) Ethvl (IRS) f1-Hydroxy-l-(4-methoxyphenvl)1-315 phenylindene-2-carboxylate. 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/ Et₂O (37 ml). The resulting p-methoxyphenyl magnesium bromide solution was added to a solution of ethyl l-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in Et₂O (300 ml) under an argon atmosphere at 0°C. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min.

The mixture was partitioned between 3M HC1 (100 ml) and

EtOAc (200 ml). The organic extract was washed successively with H₂O, aqueous NaHCO3, H₂O and saturated aqueous NaCl and dried (Na₂SO4). The solvent was removed in vacuo to provide a yellow oil which was treated with Et₂O/ 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 Et₂O/ hexanes, and the additional solid which formed (1.76 g, 75% total yield) was collected by filtration to afford the title compound.

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-21b) ELhyl—ί RS) -1- (.4-MethQxvphenyl) -3-phenylindene-2carhozylats· To a solution of ethyl (IRS) [1-hydroxy-l(4-methoxyphenyl)]-3-phenylindene-2-carboxylate (4.65 g, 12.0 mmol) in CH2CI2 (40 ml) at 0°C under an argon atmosphere was added triethylsilane (2.34 ml, 14.6 mmol), followed by boron trifluoride etherate (8.8 ml, 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 H2O, aqueous NaHCO3, H2O and i 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 Δ1 and Δ2 double bond isomers.

c) Ethvl (1RS-.2SR-,35R)-1-(4-Methoxyphenyl)-3phenylindane-2-carboxylate. To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-phenylindene-2-carboxylate (5.75 g, 15 mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg). The resulting f suspension was stirred under an atmosphere of H2 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.

d) (IRS.2RS.3SR)-1-(4-Methoxyphenvl)-3-phenylindane-230 carboxylic acid. To a solution of ethyl (IRS,2SR,3SR)1-(4-methoxyphenyl)-3-phenylindane-2-carboxylate, (5.5 g, 14.8 mmol) in EtOH (70 ml) was added 5M NaOH (9 ml, mmol). The resulting mixture was stirred under an argon atmosphere for 1 d, at which time H2O (70 ml) was added. The mixture was concentrated under reduced pressure. The aqueous residue was extracted with Et2O,

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- 22and the Et2O extracts were discarded. The aqueous phase was acidified with 6M HC1 and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O 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*C.
1E...NMR (CDCI3) : δ 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 C23H20O3 : 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 r

a) Ethvl 2-Benzovl-3-(4-hvdroxyphenyl)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%).

b) Elhyl_(2R5. 3SR) -3-(4-Hydroxyphenyl)-l-oxoindane-2carboxylate. To a mixture of ethyl 2-benzoyl-3-(4hydroxyphenyl)propenoate (0.50 g, 1.7 mmol) in CH2CI2 (15 ml) at 0°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

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-23with 3M HC1, then partitioned between EtOAc (50 ml) and 3M HC1. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O and saturated aqueous NaCl, and dried (Na2SO4) . The solvent was removed in vacuo, and the solid residue was recrystallized from EtOAc/ hexanes to afford the title compound (410 mg, 82%).

c) Ethyl—(2RS,3SR1-3-(4-t-Butyldimethylsiloxyphenyl)-1oxoindane-2-carboxylate. To a solution of ethyl (2RS,3SR)-3-(4-hydroxyphenyl)-l-oxoindane-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 HC1 and extracted with EtOAc (2x). The combined organic extracts were washed successively with H2O, aqueous NaHCO3, H2O 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.

d) Ethyl 3-(4-t-Butyldimethylsiloxyphenyl)-1-oxoindene2-carboxylate. To a solution of ethyl (2RS,3SR)-3-(4-tbutyldimethylsiloxyphenyl)-1-oxoindane-2-carboxylate (130 mg, 0.32 mmol) in CH2CI2 (3 ml) under an argon atmosphere was added 2,3-dichloro-5,6-dicyano-l,4benzoquinone (80 mg, 0.35 mmol). The resulting mixture was stirred for 2.5 h. Aqueous NaHSC>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 NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash bad ORIGINAL

-24chromatography on silica gel to afford the title compound (110 mg, 85%) .

e) Ethyl—(IRS)-3-(4-t-Butyldimethylslloxyphenyl)-1hvdroxv-l-(4-methoxvPhenvl)indene-2-carboxylate. To dry magnesium turnings (119 mg, 4.9 mmol) under an argon atmosphere was added, portionwise, a solution of pbromoanisole (0.61 ml, 4.9 mmol) in 9 : 1 Et2O/ THE (10 ml). The resulting p-methoxyphenyl magnesium bromide solution was added to a solution of ethyl 3-(4-tbutyldimethylsiloxyphenyl)-l-oxoindene-2-carboxylate (1.00 g, 2.5 mmol) in Et2O (60 ml) under an argon atmosphere at 0’C. The resulting mixture was allowed to warm to room temperature and was stirred for 5 min. The mixture was partitioned between 3M HCI and EtOAc. The organic extract was washed successively with H2O, aqueous NaHCC>3, H2O 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.

f) Ethvl 1R5).-I- (4-t-Butvldimethylsiloxyphenvl)-3-(4methoxyphenyl)indene-2-carboxylate. To a solution of ethyl (IRS)-3-(4-t-butyldimethylsiloxyphenyl)-1-hydroxy1-(4-methoxyphenyl)indene-2-carboxylate (2.5 mmol, prepared above) in CH2CI2 (10 ml) at 0°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 HCI. The mixture was extracted with

EtOAc. The organic extract was washed successively with

H2O, aqueous NaHCO3, H2O 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% Et2O/ hexanes to provide the title_

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-25compound as a mixture of Δ1 and Δ2 double bond isomers (820 mg, 67% for two steps).

g) Ethvl (IRS. 2SR..3SR) -1- (4-t-Butyldlmethyl5 siloxvphenvl) -3- (.4-methoxyphenyl) lndane-2-carboxylate.

To a solution of ethyl (RS)-3-(4-t-butyldimethylsiloxyphenyl)-1-(4-methoxyphenyl)indene-2-carboxylate (mixture of Δ1 and Δ2 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 H2 for 18 h, then was filtered through a

Γ pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (730 mg, 97%), which was used without further purification.

h) Ethvl -(IRS. 2RS, 3SR) -1- (4-Hydroxyphenyl) -3- (4methoxyphenyl)indane-2-carboxylate. To a solution of ethyl (IRS,2SR,3SR)-1-(4-t-butyldimethylsiloxyphenyl)-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 HC1 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic ’ 25 extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound (554 mg, 100%).

i) Ethyl (cis, cis)-1.3-Di(4-methoxyphenyl)indane-230 carboxylate. To a solution of ethyl (IRS,2RS,3SR)-1-(4hydroxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate (270 mg, 0.7 mmol) in acetonitrile (5 ml) at 0°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

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C

C 25 partitioned between EtOAc and dilute aqueous HC1. The organic extract was washed with saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford the title compound (40 mg, 32% based on recovered starting material).

j) (trans, trans)-1.3-Di(4-methoxyphenyl)indane-2carboxylic acid. To a solution of ethyl (cis, cis)-1,3di(4-methoxyphenyl)indane-2-carboxylate (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*C for 5 days. Water was added, and the mixture was concentrated under reduced pressure. The aqueous residue was extracted with Et2O (2x), and the Et2O extracts were discarded.

The aqueous phase was acidified with 6M HC1 and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H₂O 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°C.

¹H NMR (acetone-d6) : δ 7.25 (dd, 4H, J = 6.6 Hz, 2.1 Hz); 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+NH₄) ⁺] .

Anal. Calc, for 02₄Η22θ4 ' C, 76.99; H, 5.92.

Found C, 76.74; H 6.15.

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- 27EXAMPLE 3 (1RS, 2SR. 3SR) -1- (4-Methoxyphenvl) -3- (3.4mgthylenediQxvphenyl)indane-2-carboxylic acid

a) 2=-..(3., 4-Methyleneri.ioxyhenzoyl) benzoic acid. To a solution of 2-bromobenzoic acid (12 g, 0.06 mol) in THF (200 ml) at -100°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 10 90°C. Upon completion of the addition, the resulting

Λ· ' solution was stirred at -100’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°C. The resulting mixture was allowed to warm to -80^eC 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 Et2O and 1M HC1. The organic phase was extracted with 10% aqueous NaOH. The NaOH extract was acidified with concentrated HC1, and the combined aqueous material was extracted with Et2O. The Et2<3 c extract was dried (MgSOi) and concentrated under reduced pressure. The residue was purified by flash ( 25 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%).

b) Diethyl 2-Γ 2-(3,4-Methylenedioxybenzoyl)benzoyl30 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 Et2O (50 ml) and to this was added a solution of diethyl magnesium malonate [prepared by the method of Walker and Hauser, JACS, 68, 1386_

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-2810 r

r f 25 (1946) using magnesium (0.8 g, 33.3 mmol) and diethyl malonate (4.9 g, 30.6 mmol,] in Et20. The resulting mixture was heated at reflux for 1 h, then allowed to cool and was poured into ice-cold 10% aqueous H2SO4 (100 ml). The aqueous phase was extracted with Et2O, 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.

c) Ethvl 3- (3,4-Methylenedioxyphenyl) -l-oxoindene-2carboxylate. A solution containing diethyl 2-(2-(3,4methylenedioxybenzoyl)benzoylmalonate (crude material prepared above) in 5% aqueous Na2CO3 (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 H2O (50 ml), and the mixture was heated at reflux, cooled and concentrated 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).

d) Ethyl_QRS.1 -1-Hvdroxy-l- (4-methoxyphenyl) -3- (3.4methvlenedioxyphenyl)indene-2-carboxylate. A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9 : 1 Et2<3/ 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-(3,4methylenedioxyphenyl)-l-oxoindene-2-carboxylate (0.77 g,

2.4 mmol) in 10 : 1 Et₂O/ THF (55 ml) at 0°C. The resulting mixture was stirred at 0^eC 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 NaHCO3 and saturated aqueous NaCl and dried (MgSO4,. The

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-29solvent 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%).

e) Ethvl-.(RS) -1- (4-Methoxvphenyl) -3- (3.4-methylenedioxyphenyl) indene-2-carboxylate. To a solution of ethyl (IRS)-1-hydroxy-l-(4-methoxyphenyl)-3-(3,4methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2CI2 (10 ml) at 0’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’C for 10 min, and was then partitioned between EtOAc and 3M HC1. The organic extract was washed with saturated aqueous NaCl and dried (MgSOi). The solvent was removed in vacuo, and the residue was filtered through a pad of silica gel, eluting with CH2CI2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).

f) Ethyl(IRS. 2RS.3SR)-1- (4-Methoxyphenyl)-3-(3.4methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4methylenedioxyphenyl)-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 H2 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.

g) (IRS.2SR.3SR)-1-(4-Methoxvphenvl)-3-13, 4methylenedioxyphenvl)indane-2-carboxylic acid. To a solution of ethyl (IRS,2RS,3SR)-1-(4-methoxyphenyl)-3(3,4-methylenedioxyphenyl)indane-2-carboxylate (0.10 g,

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-300.2 mmol) in EtOH (5 ml) was added a solution of sodium hydroxide (0.10 g, 2.5 mmol) in H2O (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%).

NMR (CDCI3) : δ 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 Csi^oOs'Vs H₂O : C, 73.79; H, 5.22. Found C, 76.73; H 5.21.

EXAMPLE 4

-LIBS». 2SR, 3SRL-1- (4-FluoxQphenyl) -3,-L3, 4methvlenedioxyphenyl)indane-2-carboxylic acid

a) EthyJ—(IRS) -l-(4-Fluorophenyl) -1-hydroxy-3- (3,4mathylenedioxyphenyl) indener.2-carbQxylat£. To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (5 ml) under an argon atmosphere at 0°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 HC1 and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 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%) .

b) Ethyl_(RS) -.1 -i.4.-RJ.ugrtigh£.nylj-3c..i3.^.4-mehhylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (IRS)-1-(4-fluorophenyl)-l-hydroxy-3-(3, 4methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2CI2 (3 ml) at 0°C was added triethylsilane bad original S

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- 31 (38 gl, 0.24 mmol), followed by boron trifluoride etherate (121 gl, 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 HC1. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.

c) Ethvl.ilRS, 2RS, 3SR1-1-(4-Fluorophenyl)-3-(3.4methvlenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(4-fluorophenyl)-3-(3, 4methylenedioxyphenyl)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 H2 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.

d) (IRS, -2.SR, 3SRJ-1- (4-FluQrophenyl) -3- (3, 4methylenedioxyphenvl)indane-2-carboxylic acid. To a solution of ethyl (IRS, 2RS, 3SR)-1-(4-fluorophenyl)-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 H2O and Et2O. The aqueous phase was acidified with 3M HC1 and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from EtOAc/ hexanes. The title compound_

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-325 (

Γ ( 25 was obtained as an off-white crystalline solid (22 mg, 39%); m.p. 146 - 149*C.

²H NMR (CDC1₃) : δ 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, «7 = 10 Hz) .

MS. m/e (rel. int.) : 753 [(2M+1)⁺, 3].

Anal. Calcd. for C23H17FO4: C, 73.40; H, 4.55.

Found: C, 73.19; H, 4.45.

EXAMPLE 5 (IRS. 2SR. 3SR1-1-(3-Methoxyphenyl)-3-(3.4methvlenedioxvphenvl)indane-2-carboxylic acid

a) Ethvl (IRS)-1-Hvdroxy-l-(3-methoxyphenyl)-3-(3.4mfithvlenedioxvphenyl)indene-2-carboxylate. To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (2 ml) under an argon atmosphere at 0*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 HC1 and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O 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 (150 mg, 100%).

b) _(IRS)-1-(3-Methoxyphenyl)-3-13.4-methylenedioxyphenyl )indene-2-carboxylate. To a solution of ethyl (IRS) -1-hydroxy-1-(3-methoxyphenyl) -3-(3, 4-_

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- 33methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35 mmol) in CH2CI2 was added triethylsilane (67 μΐ, 0.42 mmol), followed by boron trifluoride etherate (213 μΐ, 1.73 mmol). The reaction mixture was allowed to stir for 30 min, at which time was added slowly 5% aqueous HC1. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSC>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 Δ1 and Δ2 double bond isomers.

c) Ethvl (RS, 2RS, 3SR)-l-(3-Methoxvphenyl)-3-(3.4methvlenedioxvphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(3-methoxyphenyl)-3-(3, 4methylenedioxyphenyl)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 H2 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.

d) jLLR'L—ZSBj_3SRL-1- (3-Methoxyphenyl) -3- (3.4methylenedioxyphenyl)indane-2-carboxylic acid. To a solution of ethyl (IRS, 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 H2O and Et2O. The aqueous phase was acidified with 3M HC1 and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with

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- 34 Η2Ο and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from Et2O/ hexanes. The title compound was obtained as a solid; m.p. 131 - 133°C.

*H NMR (CDC1₃) : δ 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, IH, J= 9 Hz).

MS m/e (rel. int.) : 777 [(2M+1)⁺, 65].

Anal. Calcd. for C24H20O5: C, 74.21; H, 5.19.

Found: C, 74.71; H, 5.47.

EXAMPLE 6 c .(IRS, 3RS) -1.3-Di- (3,4-methylenedioxyphenyl) indane-2-carbnxylic..acld

a) Ethyl (IRS)-1,L-msthyleQedlQxyphfinyl)-1hydroxyindene-2-carboxylate. To dry magnesium turnings (0.25 g, 10 mmol) under an argon atmosphere was added a solution of 4-bromo-l,2-methylenedioxybenzene (2.1 g, 10 mmol) in 1 : 10 THF/ Et2O (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

C was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-l-oxoindene-2-carboxylate (0.50 g, 2 mmol) in

1 : 4 THF/ Et2O (25 ml) under an argon atmosphere at

0°C. The resulting mixture was stirred at 0°C for 15 min, at which time 1M HC1 (50 ml) was added. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, 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%) .

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-35b) Ethyj—(RS 1.,,-,1,3,-Di- (3.4rjnethvlenedioxyphenyl) indene2 ^carboxyl at. e. To a solution of ethyl (IRS)-1,3-di(3,4-methylenedioxyphenyl)-l-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2CI2 (3 ml) at O’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 HC1, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO^) .

The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2CI2 to provide the title compound (257 mg, 92%).

c) Ethvl -(IRS, 3RS1-1.3-Di-(3.4-methylenedioxyphenyl) indane-2-carboxylate. Ethyl (RS)-1,3-di-(3,4Methylenedioxyphenyl)indene-2-carboxylate (163 mg, 0.38 mmol) was placed in MeOH (0.05 ml), and to this was added Sml2 (10 ml of 0.1M 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 Sml2 (5ml of 0.1M solution in

THF, 0.5 mmol) was added, and stirring was continued for 2 h. The reaction mixture was partitioned between Et2O and 5% aqueous Na2S2O3. The organic extract was washed with saturated aqueous NaCl and dried (MgSC>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%).

d) (IRS. 3RS)-1.3-Di-(3.4-methylenedioxyphenvl)indane2-carboxylic acid. To a solution of ethyl (IRS, 3RS)1, 3-di-(3,4-methylenedioxyphenyl)indane-2-carboxylate

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-36(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 h, allowed to cool and was concentrated under reduced pressure. To the residue was added concentrated HC1, 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°C.

^xfl. NMR (CDC1₃) : δ 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)⁺.

Anal. Calcd. for C₂₄Hi₈O₆-l/5 H₂O: C, 71.00; H, 4.52.

Found: C, 71.13; H, 4.46.

EXAMPLE 7 .(trans, trans) -1,3-Di- (3. 4-methylenedioxyphenyl) indane2-carboxylic acid

a) Ethyl—(ciSx cis)-1,3-Di-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1,3di-(3,4-methylenedioxyphenyl)indene-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 H₂ 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.

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-37b) (trans, trans)-1.3--ΡΪ-(3. 4-methylenedioxyphenyl)indane-2-carboxyllc acid. To a solution of ethyl (cis, cis)-1,3-di-(3,4-methylenedioxyphenyl)indane-2carboxylate (45 mg, 0.1 mmol) in 2 : 1 EtOH/ H2O (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 HC1, and the solid which formed was collected by filtration and dried. The solid was recrystallized from Et2O/ hexanes to afford the title compound as a light tan solid (12 mg, 30%); m.p. 188 191’C.

IlRS^....2RSu—3SR)-l-(3. 4-Methvlenedloxyphenyl) -3phenylindane-2-carbQxylic acid

a) Ethvl (IRS) -l-Hv.drQXV-l- (3.4-methvlenedioxyphenyl) 3-phenylindene-2-carboxylate. To a solution of ethyl 120 oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in

THF (35 ml) under an argon atmosphere at 0’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 HC1 and

EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO₄) . 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%).

b) Ethyl (RS)-1-(3,4-Methylenedioxyphenyl)-3-phenylindene-2-carboxylate. To a solution of ethyl (1RS)-1hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-235 carboxylate (1.03 g, 2.58 mmol) in CH2CI2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by

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-38boron 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 HC1. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCC>3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.

c) Ethyl. (IRS, 2SR, 3SR)-1-(3. 4-Methylenedioxyphenyl)3-phenylindane-2-carboxylate. To a solution of ethyl (RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2carboxylate (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 H2 overnight. Thin layer chromatographic analysis indicated that the reaction was incomplete, so additional 10% palladium on activated carbon (30 mg) was addled, and the mixture was shaken on a Parr hydrogenator at 30 psi H2 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 H2 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.

d) (IRS, 2RS. 3SR)-1-(3,4-Methylenedioxyphenyl)-3phenylindane-2-carboxylic acid. To a solution of ethyl (IRS, 2SR, 3SR)-1-(3,4-methylenedioxyphenyl)-3-_

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-39phenylindane-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 H2O and Et2O. The aqueous phase was acidified with 3M HCI and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSOi). 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°C.

Anal. Calcd. for C23H18O4: C, 77.08; H, 5.06.

Found: C, 76.60; H, 5.08.

EXAMPLE 9 (IRS. 2SR. 3SR)-l-(4-Methoxyphenyl)-3-(3.4mathvlanedioxvphenvl)-2-(tetrazol-5-yl)indane

a) (IRS. 2SR. 3SR)-1-(4-Methoxyphenyl)-3-(3.4methvlenedioxypheny1)indane-2-carboxamide. A mixture of (IRS, 2SR, 3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylic acid (250 mg, 0.64 mmol) in SOCI2 (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 NH4OH (5 ml). The solid which formed was collected by filtration, washed with H2O and dried in vacuo to afford the title compound (185 mg, 75%).

b) (IRS, 2SR, 3SR)-1-(4-Methoxvphenyl)-3-(3.4-methylenedioxyphenyl)indane-2-carbonitrile. To ice-cold DMF (1 ml) under an argon atmosphere was added oxalyl chloride (68μ1, 0.78mmol). After stirring for 5 min at

0°C, a solution of (IRS, 2SR, 3SR)-1-(4-methoxyphenyl)-_

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-4010

3-(3,4-methylenedioxyphenyl)indane-2-carboxamide (150 mg, 0.39 mmol) in DMF (2 ml) was added, and stirring was continued for an additional 10 min at O’C. The reaction mixture was partitioned between EtOAc and 3M HC1. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O, aqueous NaHCO3, H2O 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.

a ( 25

c) HRS,,. 2SR,_3SR) -1- (4-Methoxyphenyl) -3- (3. 4methvlenedioxvphenyl)-2-(tetrazol-5-yl)indane. To THF (2.5 ml) at -78°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’C for 5 min, then cooled to room temperature. To the reaction mixture was added a solution of (IRS, 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’C overnight, thin layer chromatographic analysis of the reaction mixture indicated the presence of starting material, so additional A1(N3)3 was prepared as above (1.34 mmol) in THF. To this was added the reaction mixture, and heating at 70^eC was resumed for an additional 5 h. The mixture was partitioned between EtOAc and 3M HC1. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, 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/H2O=60/40) and then o

recrystallized,· m.p. 155 - 157 C (EtOAc/ hexanes) ._

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	NMR	(CDCI3) : δ 7	.28 - 7.1	5 (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	i+H) +	] .

EXAMPLE 10 (IRS, 2SR, 3RS)-1-(2-Methoxyphenyl)-3-(3,4methvlenedioxvphenyl) indane-2-carboxylic acid

a) Ethyl (IRS) -1-Hydroxy-1- (2-methoxyphenyl) -3,- (3, 4methvlenedioxyphenyl)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/ Et2O (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)-l-oxoindene-2carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0^eC. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O 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%) .

b) Ethyl (RS) -1- (2-Methoxyphenyl) -3- (3^4rinethylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (IRS)-1-hydroxy-l-(2-methoxyphenyl)-3-(3, 4methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2CI2 (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

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-42which time was added slowly 3M HC1. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.

c) Ethyl—(IRS., ..2ELS<„,2BS) τΐ- (ZrltethQKyphenyl) -3- (3, methylenedioxyphepyl)lndane-2-carbQxylate. To a solution of ethyl (RS)-1-(2-methoxyphenyl)-3-(3,4methylenedioxyphenyl)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 H2 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.

d) (IRS. 2SR.3RS)-1-(2-Methoxvphenvl)-3-(3.4methylenedioxyphenyl)indane-2-carboxylie acid. To a solution of ethyl (IRS, 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 H2O and Et2O. The aqueous phase was acidified with 3M HC1 and extracted with EtOAc. The EtOAc extract was washed successively with H2O and saturated aqueous NaCl and dried (MgSO4).

The solvent was removed in vacuo to afford the title compound (40 mg, 49%).

NMR (CDCI3) : δ 7.37 - 6.73 (m, 11H); 5.93 (m, 2H);

5.03 (d, 1H, J = 10 Hz); 4.67 (d, 1H, J = 10 Hz); 3.70

AP 0 0 0 4 3 3

- 43 EXAMPLE 11 (IRS,_ZSEL,_3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3.4methyenedioxyphenyl)indane-2-carboxvllc acid, sodium salt

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 3hydroxyacetophenone (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, H20 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.

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 H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the

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AP Ο 00 *3 3 •44title compound (112.5 g, 97%).

c) Methyl 2.- (3-Benzylaxybenzflyl Lr 3-.13«l-methylenedloxyPhenyl)propenoatfi. A mixture containing methyl 2-(35 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 H2O. After heating at reflux for 4 h, the reaction mixture was concentrated in vacuo, and the residue was crystallized from EtOH to afford the title compound (93.5 g, 85%); m.p. 116 - 118*0.

d) Methyl—(1KS..2SR) -5-Benzyloxy-l- (3. 4-methylenedioxyohenyl)-3-oxoindane-2-carboxylate. To trifluoroacetic acid (150 ml) at 0°C under an argon atmosphere was added methyl 2-(3-benzyloxybenzoyl)-3-(3,4-methylenedioxyphenyl)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 NaHCO3, ^Η2θ 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°C.

e) Methyl 5rBenzyloxy-l-(3,4-methylenedioxyphenyl)-3oxoindene-2-carboxylate. To a solution of methyl 5benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxoindane-230 carboxylate (27.3 g, 65.6 mmol) in benzene (90 ml), cooled in an ice-H2O bath, was added 2, 3-dichloro-5,6dicyano-1,4-benzoquinone (15.4 g, 67.8 mmol). The resulting mixture was stirred at 0°C for 1 h, allowed to warm to room temperature for 1.5 h, and finally warmed to 4 0°C for 1 h. The solid which formed was removed by filtration and washed with benzene. The combined

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filtrate and washings were poured into EtOAc (200 ml) and washed successively with aqueous Na2CO3 (3x), H2O (3x), 3M HC1, H2O (3x) and saturated aqueous NaCl and dried. The solvent was removed in vacuo, 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*C.

f) Methyl (3RS)-5-Benzyloxy-3-hydroxy-3-(4-methoxy10 phenyl)-1-(3,4-methylenediQxyphenyl}.lndene-2earboaylate.

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 Et2O/THF (50 ml). The resulting 4-methoxyphenyl magnesium bromide solution was added portionwise to a solution of methyl 5-benzyloxy-l(3, 4-methylenedioxyphenyl)-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 HC1 and extracted with EtOAc. The organic extract was washed successively with H2O, aqueous NaHCO3, H2O 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.

g) Methyl (RS)-5-Benzyloxy-3-(4-methoxyphenvl)-1- (3.4methylenedioxyphenvl)indene-2-carbQXvlabe. To a solution of methyl (3RS)-5-benzyloxy-3-hydroxy-3-(430 methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indene-2carboxylate (crude material prepared above) in CH2CI2 (75 ml) under an argon atmosphere at 0°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°C, at which time the mixture was partitioned between 3M HC1 and EtOAc. The

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-46organic extract was washed successively with H2O, aqueous NaHCO3, H2O 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% Et2O/ hexanes. The title compound (8.41 g, 83% for two steps) was isolated as a mixture of Δ1 and Δ2 double bond isomers.

h) Methvl (IRS. 2RS. 3SR)-5-Hydroxy-3-(4-methoxy10 Phenyl)-1- (3.4-methylenedloxyphenylIindane-2carboxylate. To a degassed solution of methyl (RS)5-benzyloxy-3-(4-methoxyphenyl)-2-(3, 4-methylenedioxyphenyl) indene-2-carboxy late (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 H2 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 H2 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°C.

i) (IRS, 2SR, 3SR) =^-Hydroxy-3-( 4-methoxyphenyl) -130 (3.4-methylenedioxyphenyl)indane-2-carboxylic acidsodium salt. To a solution of methyl (IRS, 2RS, 3SR)-5hydroxy-3- (4-methoxyphenyl) -1- (3, 4-methylenedioxyphenyl) 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

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-47concentrated under reduced pressure. The concentrate was extracted with Et2O, and the aqueous phase was acidified and extracted with EtOAc. The EtOAc extract was washed successively with H20 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^eC (dec).

¹H NMR (MeOH-d4) : δ 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)⁺] .

EXAMPLE 12 (IRS.2SR.3RS)-3- (2-Carboxymethoxy-4-methoxyphenyl)-ΙΟ. 4-methylenedioxyphenyl)-5-(prop-l-vloxy)-lndane-2carboxyllc acid

a) 3-(Prop-l-yloxy)acetophenone. To a slurry of NaH (13.84 g, 0.58 mol) in dry DMF (50 ml) at 0°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 HC1 and extracted with EtOAc. The EtOAc extract was washed successively with; H2O, 10% aqueous NaOH and then brine. After drying (MgSO4), filtration and evaporation gave the title compound (65 g, 98%) as a yellow oil which was used without further purification.

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-48b) Methyl_3-(Prop-l-yloxy)benzoyl acetate. To a suspension of NaH (12 g, 0.5 mol) in dry dimethyl carbonate (50 ml) was added slowly a solution of 3(Prop-l-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 HC1 and extracted with EtOAc. The EtOAc extract was washed successively with; H2O, 5% aqueous NaHCO3, H2O and brine. After drying (MgSO4), filtration and evaporation gave a yellow oil (82 g, quantitative) which was used without further purification.

c) Mfithvl-(IRS.2SR)-1- (3.4-Methylenedioxyphenyl)-5iprop-l-vloxv)-3-oxo-indane-2-carboxylate. To a solution of methyl-3-(Prop-l-yloxy)benzoylacetate (10 g, 4.2 mmol) in benzene (50 ml) was added 3,4-methylene dloxybenzaldehyde (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 hr. and the volatiles removed in vacuo to give methyl (Z)-3(3, 4-methylenedioxyphenyl)-2-[3-(prop-l-yloxy)benzoylJpropenoate as a yellow oil. This residue was dissolved in trifluoroacetic acid (50 ml) and the mixture stirred at room temperature for 20 min. . The trifluoroacetic acid was removed in vacuo to give the title compound as a dark oily residue (16 g) which was used in the next step without purification.

¹H NMR (CDCI3) δ inter alia 7.85 (1H, s); 7.56-7.30 (3H, m); 7.08-7.15 (1H, m); 6.95 (1H, dd, J=8, 2Hz) ;

6.78.

d) Methyl-3- (3. 4-Methyleneriioxyphenyl)-6- (prop-l-yloxy) 1-oxo-indene-2-carboxylate. Methyl (IRS, 2SR)-l-(3,4methylenedioxyphenyl)-5-(prop-l-yloxy) -3-oxo-indane-2BAD ORIGINAL &

AP Ο Ο Ο 4 3

-493 carboxylate (16 g, crude from previous experiment) was dissolved in dioxan (150 ml) and DDQ (22 g, 0.097 mol) added. The mixture was refluxed for 2 h. then cooled, filtered and the solvent removed in vacuo. 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 (5.2 g, 31% over two steps); m.p. 125-126^eC.

e) Methyl-(IRS)-1-(2-Benzyloxy-4-methoxyphenyl)-1hvdroxv-3-(3.4-methylenedioxyphenyl)-6-(prop-1yloxy)indene-2-carboxylate. To dry magnesium turnings (0.15 g, 6.25 mg. atoms) under an argon atmosphere was added portionwise, a solution of 2-benzyloxy-4-methoxy15 bromobenzene (for preparation see below) (1.80 g, 6.15 mmol) in 5% THF/ether (7 ml). The resulting 2benzyloxy-4-methoxyphenyl magnesium bromide was added to a solution of methyl-3-(3,4-methylenedioxyphenyl)-6(prop-l-yloxy)-l-oxo-indene-2-carboxylate (1.5 g,

4.1mmol) in Et₂O (65 ml) under an argon atmosphere at O^eC. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min. The mixture was partitioned between 3M HC1 (30 ml) and EtOAc (75 ml).

The organic extract was washed successively with; H₂O, aqueous NaHCO3, H₂0 and saturated aqueous NaCl and dried (Na₂SO4). The solvent was removed under reduced pressure, and the residue purified by flash chromatography on silica gel (eluant: EtOAc/hexane, 30:70) to afford the title compound as a pale-yellow oil (1.4 g, 59%).

f) Methyl-(RS)-3-(2-Benzyloxv-4-methoxvphenvl)-1-(3.4methylenedioxyphenyl)-5- (prop-l-vloxv)indene-2-carboxv1 ate. To a solution of (1.35 g, 2.33 mmol) in CH₂C1₂ 35 (20 ml) at 0°C under an argon atmosphere was added triethylsilane (0.47 ml, 2.94 mmol), followed by boron__

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-50trifluoride etherate (1.4 ml, 11.4 mmol). The resulting solution was stirred at O*C for 10 min, and was then partitioned between 1M HC1 and EtOAc. The organic extract was washed successively with; Η₂Ο, 5% aqueous

NaHCO3, Η₂Ο and brine. After drying (Na2SO₄) the solvent was removed in vacuo, and the product purified by column chromatography on silica gel (eluant: EtOAc/hexane, 25:75). The title compound (as a single undefined double bond isomer) was obtained as yellow oil (0.65 g, 50%).

e ¹⁰

g) Methvl-(IRS,2RS. 3RS)-3-(2-Hydroxy-4-methoxyphenyl)-13-3^-4-methvlenedloxvphenvl) -5- (prop-l-yloxy) lndane-2carboxylate. Methyl-(RS)-3-(2-benzyloxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-l-yloxy)15 indene-2-carboxylate (0.64 g, 1.13 mmol) was dissolved in a small volume of EtOAc and EtOH (25 ml) added followed by 10% palladium on activated carbon (0.2 g). The resulting solution was stirred under an atmosphere of hydrogen for 10 days and filtered. The filtrate was concentrated under reduced pressure and the product purified by column chromatography on silica gel (eluant; EtOAc/hexane, 30:70) to give the title compound as a c colorless solid (0.21 g, 39%); m.p. 155-156*0.

h) Methyl-(IRS.2RS.3RS)-3-(2-Carboethoxymethoxy-4methoxyphenyll -1- (3.4-methylenedioxyphenyl)-5-(prop-lyloxy) indane-2-carboxylate. A solution of methyl(1RS,2RS,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxy30 late (0.05 g, 0.11 mmol) in dry DMF (1 ml) was added to

NaH (4 mg, 0.17 mmol) in a small volume of dry DMF. The mixture was stirred at room temperature for 10 min. and ethyl bromoacetate was added (0.016 ml, 0.14 mmol).

After 20 min., the reaction was quenched with 3M HC1 and extracted with EtOAc. The EtOAc extract was washed with water then brine, dried (MgSO4), fitered and evaporated.

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-51 C ίο C

Ο

The product was purified by column chromatography on silica gel (eluant: EtOAc/hexane, 30:70) to give the title compound as pale yellow oil (0.05g, 85%).

i) (IRS. 2SR. 3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-ΙΟ, 4-methvlenedloxvphenvl)-5-(prop-l-vloxy)indane-2carboxyllc acid. To a solution of methyl-(IRS,2RS,3RS)3-(2-carboethoxymethoxy-4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2carboxylate (0.05 g, 0.089 mmol) in EtOH (1 ml)(warming neccessary) was added 6M NaOH (0.089 ml, 0.53 mmol). After stirring overnight the product was partitioned between EtOAc and 3M HC1. The organic extract was washed with H2O and then brine, dried (MgSO4), filtered and evaporated to give a colorless oil. The product was crystallized from Et2O/hexane to give the title compound as an off-white solid (0.03 g, 65%); m.p. 195-198*C.

¹H NMR [(CD3)2CO] δ7.17 (IH, d, J=9.1Hz); 6.8-6.71 (5H, m); 6.55-6.47 (3H, m); 5.94 (2H, s); 4.97 (IH, br. d); 4.73 (IH, d, J=16.5Hz); 4.63 (IH, d, J=16.5Hz); 4.52 (IH, d, J=7Hz); 3.80-3.76 (2H, m); 3.76 (3H, s, ; 3.483.35 (IH, br. m); 1.65 (2H, sextet, J=7.4Hz); 0.92 (3H, t, J=7.4Hz).MS : 538 [(M+NH4)⁺].

Anal. Calc, for C29H28 θ9ΐ C, 66.92; H, 5.42.

Found C, 67.37; H, 5.32.

EXAMPLE ,12a

Preparation of 2-Benzyloxy-l-bromo-4-methoxybenzene.

a) l-Bromo-2-hydroxy-4-methoxvbenzene. 3-Bromo-2hydroxy-6-methoxybenzoic 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°C for 1 h. On cooling, the product was partitioned between Et2O and 3M

HC1. The organic extract was washed with water and brine then dried (MgSOkj), filtered and evaporated to give the title compound as a light-brown oil (4 g, 97%). This

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-52material was used without further purification.

!h NMR (CDCI3) δ 7.32 (1H, d, J=9Hz); 6.60 (1H, d, J=1.5Hz), 6.43 (1H, dd, J=9,1.5Hz).

b) 2-Benz vloxy-l-bromo-4-niethoxybenzene. To a suspension of NaH (1.01 g, 0.042 mol) in dry DMF (ml) at 0°C was added solution of l-bromo-2-hydroxy-4methoxybenzene (7 g, 0.035 mol). After stirring at room temperature for 30 min. the solution was cooled to 0*C and benzyl bromide (6.24 ml, 0.052 mmol) added. The mixture was warmed to room temperature over 20 min. and then quenched cautiously by the addition of 3M HC1 and extracted with EtOAc. The EtOAc extract was washed successively with; H2O, 5% aqueous NaHCO3, H2O and finally brine. After drying (MgSO4) filtration and evaporation gave a dark colored oil. The product was purified by flash column chromatography (eluant: EtOAc/hexane, 20:80) to give the title compound as a colorless oil (7.5 g, 73%).

*H NMR (CDCI3) δ 7.50-7.25 <6H, m); 6.51 (1H, d,

J=1.5Hz); 6.39 (1H, d, J=9Hz); 5.09 (2H, s); 3.72 (3H, s) .

EXAMPLE 13 (IRS, 2SR, 3RS)-3-f2-(3-Hvdroxvprop-l-vloxv)-4-methoxy25 Phenyl)-1- (.3. 4-methvlenedioxyphenyl)-5- (prop-l-yloxy)indane-2-carboxyllc acid, dicyclohexylamine salt

Methyl (IRS, 2RS, 3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-l-yloxy)30 indane-2-carboxylate (0.14g, 0.29mmol) in dry DMF (1 ml) was added to NaH (9mg, 0.38mmol) in a small volume of dry DMF. The mixture was stirred at ambient temperature for 20 min. then 3-bromopropan-l-ol (37μ1, 0.41mmol) was added. After stirring for lh. the product was partitioned between 3M aqueous HC1 and ethyl acetate.

The organic layer was washed with water then brine, then

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-53dried (MgS04 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide methyl (IRS, 2SR, 3RS)-3-(2-(3-Hydroxyprop-lyloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5(prop-l-yloxy)indane-2-carboxylate (O.lg, 65%)(^H-NMR indicated some epimerization had occurred at C-2). This material was used without further purification. Methyl (IRS, 2SR, 3RS)-3-(2-(3-Hydroxyprop-l-yloxy)-4-methoxyphenyl] -1- (3,4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylate (0.04g, 0.075mmol) was dissolved in methanol (2ml) and aqueous potassium hydroxide added (2M, 0.22ml, 0.44mmol). 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 (MgSO4 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 12mg of free acid which was converted to its dicyclohexylamine salt, m.p. 110-112*C.

EXAMPLE 14 (IRS. 2SR. 3RS)-3-Γ2-(l-Carboxyeth-2-yloxy)-4-methoxyphenyll-1-(3.4-methylenedioxyphenyl)-5-(prop-l-yloxy) indane-2-carboxylic acid, bis-dicyclohexylamine salt (IRS, 2SR, 3RS)-3-[2-(3-Hydroxyprop-l-yloxy) 4-methoxyphenyl]-1-(3, 4-methylenedioxyphenyl)-5-(prop-lyloxy) indane-2-carboxylic acid (0.07g, 0.13mmol) was dissolved in dry dichloromethane (0.5ml) and Dess-Martin periodinane (0.07g, 0.17mmol) added in dry dichloromethane (1ml). After 2h. 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 (MgSO4 anhydrous), filtered and evaporated to give an oil which

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-54was used without purification. The crude product was dissolved in t-butanol (5ml) and to this was added a solution of sodium chlorite (18mg, 0.2mmol) and sulfamic acid (21mg, 0.22mmol) in water (1.5ml). After lh.

stirring at ambient temperature the product was extracted into ethyl acetate. The organic layer was washed with water then brine then dried (MgSO4 anhyd.) filtered ^nd evaporated to give an oil. The product was purified by column chromatography on silica-gel (eluant:

ethyl acetate/hexane/31 acetic acid} f.o give 12ag of free acid which was converted to its bis-dicyclohexylami.ne salt,

m.p. 160 - 162'C.

MS (exact mass) K⁺* : 534.1879 (free di-acid) (Δ = +1.1 mDa for ^-30^30θ9^

By the methods given above, the following compounds were aiade:

EXAMPLE 15 (IRS)-1-(4-Methoxvphenvl)-3-phenyllndene-2-carboxylic acid

m.p. 191 - 193*C.

Anal. Calcd. for C23H18O3: C, 80.68; H, 5.30.

Found: C, 80.54; H, 5.33.

EXAMPLE 16 (trans, trans)-1.3-Dlphenylindane-2-carboxylic acid

m.p. 164 - 165°C.

MS (m/e) : 332 [(M+NH4)⁺).

EXAMPLE 17 (IRS, 2RS, 3SR)-l-(4--HvdrQXVPhenvl)-3-phenylindane-2carboxyllc acid

MS (m/e) : 331 [(M+H)⁺).

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-55EXAMPLE 18 (IRS, 2RS, 3SR)-1-(IrCarboxyphenyl) -3-phenvllndane-2carboxvlic acid

MS (m/e) : 359 [(M+H)⁺J.

EXAMPLE 19 .(IRS, 2RS, 3SR)-1-(3-Methoxvphenyl)-3-phenyllndane-2carboxvllc arid

MS (m/e) : 362 [(M+NH₄)⁺J.

EXAMPLE 20 (IRS., 2RS. 3SR)-1-(4-Ethylphenyl)-3-phenyllndane-2carboxylic acid

m.p. 163 - 164°C.

MS (m/e) : 360 l(M+NH₄)⁺],

Anal. Calcd. for C24H22O2: C, 84.18; H, B.<a.

Found: C, 84.24; H, 6.73.

EXAMELE_21 (IRS. 3RS)-1.3-Diphenyllndane-2—carboxy1ic acid

m.p. 210-211^eC.

EXAMELE-22 (IRS. 2RS. 3SR)-1-(4-But-4-yloxyphenyl)-3-(425 methoxyphenyl)indane-2-carboxylic acid

1h NMR (CDCI3) : δ 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).

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-56EXAMELE 23

-(IRS. 2RS. 3SR)-1-(4-Acetamldophenyl)-3-(4methoxvphenyl)lndane-2-carboxvllc acid

m.p. 231 - 232 C.

MS (m/e, rel. int.) : 803 I(2M+1)⁺, 100J.

Anal. Calcd. for C25H23NOVI/2 H2O: C, 73.12; H, 5.85; N, 3.41. Found: C, 72.92; H, 5.61; N, 3.24.

EXAMPLE 24

-(IRS, 2RS. 3SR)-1-(4-Aminophenyl) -3- (4-methoxyphenyl) indane-2-carbQxvllc acid, dlcyclohexylamlne salt

m.p. 187 - 190*C.

MS (m/e, rel. int.) : 1076.2 [<2M+1)⁺, 25].

EXAMPLE 25 .(IRS, 2SR, 3SR)-l-(4-Hydroxyphenyl)-3-(3.4methv.lenedioxvphenyl) indane-2-carboxylie acid

m.p. 94 - 96 C.

MS (m/e) : 392.4 ((Μ+ΝΗ₄)⁺].

EXAMPLE 26 .(IRS. 2RS. 3SR)-1-(3.4-Dlmethoxyphenyl)-3-(4methoxvphenyl)indane-2-carboxylic acid

m.p. 126 - 128*C.

MS (m/e, rel. int.) : 807 [(2M+1)+, 35]; 403 [(M-H)“,

100].

Anal. Calcd. for C25H24O5: C, 74.24; H, 5.98. Found: C, 74.10; H, 5.99.

EXAMPLE 27 (IRS, 2RS, 3SR1-1-(3.4-Methylenedioxyphenyl)-3-(4methylthiophenyl)indane-2-carboxylic acid

MS (exact mass) : (M-)⁺ = 404.1074 (Δ = +0.8 mDa for 35 θ2₄Η20θ4δ) .

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- 57 EXAMPLE2A (IRS, 2RS, 3SR)-5~Methoxy-3-(4-methoxyphenyl)-1-(3.4mebhylenedioxyphenyl)indane-2-carboxvlic acid

m.p. 129-131°C.

MS (m/e) : 441.2 ((M+Na)⁺].

EXAMPLE 29 (IRS. 2SR. 3SR)-1.3-Bls(3,4-methylenedloxyphenyl)-5hydroxylndane-2-carboxylic acid

MS (m/e) : 436.2 [(M+NH₄)⁺J.

EXAMPLE .,3.Q (IRS, 2SR. 3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl) 1-(2-methoxy-4.5-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2tcarboxylie acid

Methyl (IRS, 2RS, 3SR)-5-Hydroxy-3-(2-methoxymethoxy-4-methoxyphenyl)-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’C .

Anal. Calc, for C3QH3QO1Q: C, 65.45; H, 5.49.

Found: C, 65.38; H, 5.49.

EXAMPLE 31 (IRS, 2SR, 3RS)-3-(2-Methoxymethoxvl-4-methQxyphenyl)-ΙΟ, 4-methylenedioxvphenvl) -5- (prop-l-YlPXV).indane-2carboxylic acid

m.p. 161 - 163°C.

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EXAMPLE 32 (IRS. 2 SR. 3RS)-3-(2-Hvdroxy-4-mPthoxyphenyl)-l-(3.4methvlenadiQJtvphenyl) -5- (prop-l-yloxy) lndane-2carboxylic acid 5 (exact mass) M+· : 462.1678 (Δ = -0.4 mDa for C27H26O7)

EXAMPLE 33 .(IRS. 2SR. 3SR)-3-(2-Carboxymethoxy-4-methoxvphenyl)-l.f _(2-prop-l-vloKVl-4.5-methvlenedloxypheny 1)-5-(prop-1 10 vloxv)indane-2-carboxylic acid

Anal. Calc, for C3₂H340io’0-5 H₂O: C, 65.41; H, 6.00. Found: C, 65.27; H, 5.99. m.p. 196 - 197*C.

EXAMPLE 34 .1 IRS.- 2SR. 3RS) -1- (2-CarboxvmethQxy-4.5-methvlenediPXYPhenvl)-3-(4-meth0XVPhenvl)-5-(prop-l-yloxy)lndane2-carboxylic acid

ME (DCI NH3) m/e : 538.2 <M+NH3)+, 520.2 (M+H)+ (exact mass) M+· : 520.1733 (Δ = 0.0 mDa for C^H^Og)

EXAMPLE 35 (IRS, 2SR, 3RS)-1-(S.4-Methvlenedioxyphenyl)-3-f(2-propItvIqxv)Phenvll-5-(Prop-l-vloxv)indane-2-carboxylic acid

m.p. 179 - 180‘C.

MS (DCI CH₄) m/e : 503.2 (M+C₂H₅)⁺, 474.1 (M+H) ⁺ (exact mass) M⁺- : 474.2034 (Δ = +0.8 mDa for ^c29^H30°6>

EXAMPLE 36 (IRS. 2SR. 3RS)-3-(2-Hydroxyphenyl)-1-(3, 4-methylenedioxvphenvl)-5-(prop-l-vloxv)indane-2-carboxylic acid

m.p. 97 - 98*C.

MS (exact mass) M*· : 432.1568 (Δ = +0.5 mDa for

C₂ 6^h24°6>

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- 59 EXAMPLE 37 (IRS. 2SR. 3RS)-3-(2-Carboxymethoxyphenyl)-1-(3.4methylenedioxvphenyl)-5-(prop-l-yloxy)lndane-2carboxylic acid 5

m.p. 169-17O°C.

Anal. Calc, for ^28Η₂6θθ·0.25 Η2θ^: C, 67.94; H, 5.40. Found: C, 67.75; H, 5.37.

EXAMPLE 38 (IRS, 2SR. 3RS)-3-(2-Benzyloxy-4-methoxyphenyl)-1-(3.4methvlenedioxvphenvl)-5-(prop-l-vloxv)lndane-2carboxylic acid

ME (exact mass) M⁴· : 552.2149 (Δ = -0.1 mDa for

C34H32O7)

EXAMPLE 39 (IRS, 2SR. 3RS)-3-f2-(2-Hydroxyeth-l-vloxy)-4methoxvphenvll-1-(3,4-methylenedloxyphenyl)-5-(prop-lyloxy) indane-2-carboxylic acid, dlcyclohexylamlne salt

m.p. 182-184’C.

Anal. Calc, for C^HssNOg: C, 71.59; H, 7.77;

C N, 2.04. Found: C, 71.67; H, 7.66; N, 2.42.

EXAMPLE 40 (IRS.2SR.3RS)-3-(2-Ethoxy-4-methoxyphenyl)-1-(3,4methylenedioxyphenyl.) -5- (prop-l-yloxv) indane-2carfroxyllc acid

Anal. Calc, for C29H30O7: C, 71.01; H, 6.16;

Found: C, 70.71; H, 6.01.

EXAMPLE 41 (IRS. 2SR, 3RS)-3-f4-Methoxv-2-(prop-l-vloxv)1-1-(3.4Methylenedioxvphenvl)-5-..(prop-l.rvlQxyllndane.-2carboxylic acid 35

Anal. Calc, for C3QH32O7: C, 71.41; H, 6.39;_

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-60Found: C, 71.43;

H, 6.31.

EXAMPLE 42 (IRS, 2SR, 3RSL^3-f4-Methoxy-2-(prop-2-yloxy)phenyn-l-(3-,.4-Methvlenedioxvphenyl) -5- (prop-l-yloxy) lndane-25 carboxylic acid

m.p. 75-79’C.

EXAMPLE 43 .(IRS, 2SR, 3RSi-3-.I4-MethQxyr2.-J2-methylproprl-yloxy) 10 phenvll-1-(3.4-Methylenedloxyphenyl)-5-(prop-1yloxy) indane-2-carboxylic, acid

m.p. 85-89’C.

EXAMPLE 44 (IRS, 2 SR. 3RS)-3-f4-Methoxy-2-(3-methylbut-l-yloxyIPhenvll-1- (3^4-methvlenedloxyphenyl)-5- (prop-l-yloxy) lndane-2-carboxvllc acid, dicylohexylamine salt

m.p. 150-155*C.

EXAMPLE 45

HRS. _2SR. 3RS) -3- f 4-Methoxy-2- (3-pyr idyl methoxy) Phenvll-1-(3.4-methvlenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid.

Anal. Calc, for C33H3iNO7*0.5H2O: C, 71.02; H, 5.78;

N, 2.51; Found: C, 71.02; H, 5.53; H, 2.30.

EXAMPLE 46 (IRS, 2SR, 3RS)-3-f.A-Methoxv-2-(4-Pvrldylmethoxy)phenyl!-1-(3.4-methylenedioxyphenyl)-5-(prop-l-yloxy)30 indane-2 r-barhbxylic-acldx.

Anal. Calc, for C33H31NO7O.5H2O: C, 71.02; H, 5.78;

N, 2.51; Found: C, 70.89; H, 5.59; H, 2.37._

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-61 EXAMPLE 47 (IRS. 2SR.3RS)-3-f 4-Methoxy-2-(2-pyridylmethoxy1 phenvll-1-13,4-methvlenedioxyphenyl)-5-(prop-l-yloxy)5 m.p. 153-155’C.

EXAMPLE 48

J1RS.2SR_.3RS)-3-f2-(Hept-l-vloxy)-4-methoxyphenyl1-1(3.4-methylenedloxyphenyl)-5-(prop-l-yloxy)lndane-2carboxyllc acid

m.p. 70-73’C.

EXAMPLE 49 (IRS. 2SR. 3RS)-3-f4-Methoxy-2-(5-tetrazolylmethoxy) phenyll-1-(3.4-methylenedioxyphenyl)-5-(prop-l-yloxy)15 indane-2-carboxyllc acid.

m.p. 102-105’C.

EXAMPLE 50 (1RS.2SR.3RS)-3-(2-Cyanomethoxy-4-methoxyphenyl)-1-(3.420 methylenedloxyphenyl)-5-(prop-l-yloxy)lndane-2carboxyllc acid

m.p. 199-201’C.

EXAMPLE 51 (IRS.2SR.3RS)-3-(2-Carboxamidomethoxy-4-methoxyphenyl)1-(3.4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2carboxylic—acid

Anal. Calc, for C29H29NO8O · 5C4H8O: C, 67.02;

H, 5.99; N_z 2.52; Found: C, 67.76; H, 5.96;

H, 2.56.

EXAMPLE 52 (IRS. 2SR, 3 SR)-5-Acetamido-l,3-bis(3.4-methvIenedioxyphenyl)lndane-2-carboxvlic acltL·.

MS m/e : 460 [ (M+H)+] .

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- 62 EXAMPLE 53 (IRS, 2SR, 3SR)-5-Amln.o-l. 3-bls (3.4-methylenedloxyphenvl)-indane-2-carboxvlate, dicyclohexylamine salt.

MS m/e : 418 [(M+H)⁺).

EXAMPLE 54 (IRS.2SR.3RS)-3-(2-(3-Carboxyphenyl)-4-methoxyphenyl1-1(3,4-methvlenedloxyphenyl)-5-(prop-l-yloxy)lndane-2carboxy lie .. acid

a) Ethvl 3-ftri-(but-1-vl)stannyl)benzoate

Ethyl 3-bromobenzoate (2.0 g, 8.7 mmol), hexabutyldistannane (5.51 ml, 10.9 mmol), tetrakis(triphenyl15 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%) .

b) Methyl—(!RS.2SR.3RSl-3-f2- (3-carbomethoxvphenyl) -4methoxyphenvll-1- (3.4-methvlenedioxvphenyl)-5-(prop-125 ylpxy).indane-2-carbQxylate

Methyl (IRS,2SR,3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(propl-yloxy) indane-2-carboxylate (0.118 g, 0.19 mmol), lithium chloride (0.058 g, 1.37 mmol), tetrakis(triphenylphosphine) palladium (0) (0.018 g, 0.016 mmol) and ethyl 3-[tri-(butyl-l-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 bad original

AP 0 0 0 433

to be a mixture of two components by TLC. Purification by column chromatography on silica-gel gave a less polar fraction: methyl (IRS,2SR, 3SR)-3-[2-(but-l-yl)-4methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-15 yloxy)indane-2-carboxylate (0.038 g) which was obtained as a colorless oil. The title compound was the more polar component (0.08g) which while contaminated with tin residues (¹H-NMR) was used without further purification.

c) (1RS.2SR.3RS)-3-f 2-(3-Carboxyphenyl)-4-methoxy(~ phenyl1-1-(3,4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid

Methyl (IRS,2SR,3RS)-3-[2-(3-Carbomethoxyphenyl)-4methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-lyloxy) indane-2-carboxylate (0.08g, crude) was dissolved in propan-2-ol (1 ml) and aqueous sodium hydroxide (1M, ml ,1 mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3Maqueous hydrochloric acid and extracted with ethyl acetate (3x). The combined organic extract was purified

O by column chromatography on silical-gel (eluant: 30%

EtOAc/hexane/5%AcOH) to give the title compound as a

C 25 colorless solid (20 mg)

m.p. 257-268°C.

EXAMPLE 55 (IRS.2SR.3SR)-3-i2-(Rut-l-vl)-4-methoxyphenvl)-1-(3.430 methylenedioxyphenvl)-5--(prop-l-vlPxy)indane-2carboxvllc acid, dicyclohexvlamlne salt

Methyl (IRS,2SR,3SR)-3-(2-(But-l-yl)-4-methoxyphenyl)-ΙΟ, 4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-235 carboxylate (0.038g, 0.074 mmol) was dissolved in propan-2-ol (1 ml) and aqueous sodium hydroxide (1M,_

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-640.75 ml,0.75 mmmol) 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.

m.p. 179-182°C.

Anal. Calc, for C₄₁H5₃NO₈: C, 71.59; H, 7.77;

N, 2.04. Found: C, 71.67; H, 7.66; N, 2.42.

EXAMPLE 56

11RS, 2SR, 3SRl-J-(4.rMfithoxy-2-phenylpheQyll,rl.-i3_<jlr.

methylenedloxyphenylLr-5-- iprap-l-yloxy) lndang-215 carboxylic acid

a) Methyl—(1RS.2RS,3SR)-3-(4-Methoxy-2-phenylphenyl)-1-L3^J-methvlenediQXVPhenvl) -5- (prop-l-yloxy) lndane-2carboxylate

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 (IRS,2RS,3RS)-3-(4-Methoxy-2-trifluoro25 methanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)5-(prop-l-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol) and tri(but-l-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 (MgSO4 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 bad original

AP 0 0 0 4 3 3

-65solid. (92 mg, 86%).

b) (1RS.2SK, 3SR1 -3-_(4-Methoxv-2-phenylphenyl) -1- (3.4methvlenedioxvphenvl)-5-(prop-l-yloxy)lndane-25 carboxylic acid

To a solution of Methyl (IRS,2RS, 3SR)-3-(4-Methoxy-2phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-lyloxy) indane-2-carboxylate (80 mg, 0.12 mmol) in dioxane φ 10 (2 mL) was added 1M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was heated to reflux for 48 h, then θ 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 (MgSO4 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%).

m.p. 199 - 200’C.

¹H NMR (CDC1₃) δ 7.18-7.09 (m, 6H); 6.85 (dd, 1H, J

Ο = 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 = & 25 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). .

MS m/e : 540 (M+NH4)⁺.

Anal. Calc, for C33H3QO5 · 3/4 H₂O: C, 73.93;

H, 5.90. Found: C, 74.12, H, 5.80.

EXAMPLE 57 (IRS. 2SR. 3SR)-3-f2-f(E)-2-Carboxyethen-l-yll-4methoxyphenyl1-1- (3, 4-methylenedioxvph.envU -5.- (prop-lyloxy ) lndane-2-carboxylic acid

BAD ORIGINAL _e AP O 00 43 3

-66a) Methvl 11RS-.. 2SR, 3SR)-3-(2-((E)-2-carbomethoxyethenrlcyllrlrmfithoxyphenyll-1- (3,.,4ring thyl enediQxvDhenylL-5_-_iprQD-l-vlQxy) lndane-2-carboxylate.

1,3-bis(diphenylphosphino)propane (0.066 mmol), tris(dibenzylideneacetone)dipalladium(O) (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 (IRS, 2SR, 3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)1-(3, 4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2carboxylate (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 *H 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 chroma-tography ( silica gel, gradient elution:

10 % to 20% ethyl acetate/hexanes) to afford the title compound as a tan solid. (87 mg, 62%).

²H NMR (CDC1₃) : δ 8.17 (d, 1H, J = 15.7 Hz); 7.44 (d, 1H, J = 8.7 Hz), 7.11-7.07 (m, 2HJ; 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).

bad original

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-67b) (lRSu-.2SR. 3SR)-3-f2-f (E)-2-Carboxyethen-l-yl1-4methoxyphenvllr·.!- (3, 4-methvlenedioxyphenyl) -5- (prop-lyloxy ) lndane-2-carboxylic acid.

To a solution of methyl (IRS, 2SR, 3SR)-3-[2-[(E)-2carbomethoxyethen-l-yl]-4-methoxyphenyl]-1- (3,4methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2carboxylate (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 HCI and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the title compound was obtained as a white solid (73 mg, 96%).

¹H NMR (CDC1₃) : δ 8.32 (d, 1H, J = 15.6 Hz); 7.246.55 (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);

c 1.00 (t, 3H, J = 6.9 Hz).

MS m/e : 517 [(M+H)⁺l.

£ ' 25 Anal. Calc, for C3qH2qOq : C, 69.76; H, 5.46.

Found: C, 69.73, H, 5.26.

EXAMPLE 58 (IRS. 2SR, 3SR)-3-f2-(2-Carboxyeth-l-vl)-4-methoxyphenyll-1-(3.4-methylenedioxvphenyl)-5-(prop-l-yloxy)30 indane-2-carboxvlic acid.

To a solution of (IRS, 2SR, 3 SR)-3-[2-[ (E)-2-carboxyethen-l-yl]-4-methoxyphenyl]-1-(3, 4-methylenedioxyphenyl)-5-(prop-l-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

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-68stirred 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.

	5	xa.NMR (CDC13) : δ 6.99 (d, IH, J = 8.6 Hz); 6.78-6.66 (m, 7H); 6.23 (b s, IH); 5.88-5.87 (m, 2 H); 4.88 (d, IH, 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, IH); 2.68-2.51 (ra, 2H,; 1.65 (sextet, 2H, J = 7.0 Hz); 0.89
0	10	(t, 3H, J = 7.0 Hz).
V/		MS (exact mass) M+· : 518.1930 (Δ - +1.1 mDa for
0		C27H26°7) By the methods given above in Examples 54 to 58, the following compounds were made.
	15	EXAMPLE 59 ilRS,2SR,3RS)-3-(2-CarboxymethyIthl0-4-methoxyphenyl)-1-

„(3. 4-methvlenedloxvphenvl) -5- (prop-l-yloxy) lndane-2carboxyllc acid

m.p. 242-246‘C (dec).

EXAMPLE 60 (IRS, 2SR, 3SRl-J--i4-MeLhQxy-2-(prop-2-en-l-yl)phenyl 1 O 1-.(3. 4-meLhvlenedioxvphenvl)-5- (prop-l-yloxy) indane-2carboxylic.acid V.’ 25 m. p. 126-127°C.

(exact mass) M⁺· : 486.2021 (Δ = +2.1 mDa for Οβοϊ^Οθ)

EXAMPLE 61 (IRS. 2SR. 3SR1-3-f4-Methoxy-2-(prop-l-yl)phenyl)-ΙΟ. 4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-230 carboxylic acid

m.p. 155-156°C.

Anal. Calc, for C30H32O6 : C, 73.75; H, 6.60.

Found: C, 73.45, H, 6.43.

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-69EXAMPLE 62 (1RS,.....2SR. 3RS.Lc3- f2-CarbQxv-4-methoxyphenyll-l- (3. 4methvlenedioxvphenvl)-5-(prop-l-yloxy)indane-2carboxylic acid.

Anal. Calc, for C28H26^O8 ^{: c}< 68.56; H, 5.34.

Found: C, 68.61, H, 5.58.

EXAMPLE 63 .(IRS, 2SR, 3 SR)-3- f2- (2-Hvdroxyethyl) -4-methoxyphenyl 1 1-(3,4-methvlenedloxvphenvl)-5-(prop-l-yloxy)lndane-2xjk 10 carboxylic acid vi/ J (exact mass) M⁺· : 490.1994 (Δ = +0.3 mDa for C29H30O7)

EXAMPLE 64 (IRS, 2SR, 3 SRI-3-(2-Carhoxymethyl-4-methoxyphenyl)-115 (3, 4-methylenedioxvphenvll-5-(prop-l-yloxy)lndane-2carboxylic acid (exact mass) M⁺- : 504.1788 (Δ = -0.4 mDa for C29H28O8)

EXAMPLE 65 (IRS, 2SR, 3SR1-3-f2-(3-Hvdroxyprop-l-yl)-4-methoxyDhenvll-1-(3.4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid c

MS (exact mass) M⁺· : 504.2143 (Δ = +0.5 mDa for

C 25 C30H32O7)

EXAMPLE 66 (IRS. 2SR,_3 SR)-5-(4-Carboxyphenyl)-1.3-bis(3,4methylenedioxyphenyl)l-indane-2-carboxylic acid.

m.p. 230-231°C.

EXAMPLE . 62 (IRS, 2SR, SSRl^S-(4-Ben2.vltxyphenyl-Lcl,3-bis (3,.4methylenedioxyphenyl)indane-2-carboxyllc acid.

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-70EXAMPLE 68 (IRS, 2SR, 3SR1-5-([4-Hvdroxyphenyl)-l.3-bis(3.4methylenedloxvphenvl)lndane-2-carboxyllc acid.

MS m/e : 512 [(M+NH4)+J.

EXAMPLE., 6,S .itrans, trans-lxX.5-txla_t3xA-methylenedlQ&ypheny.ll.x indane-2-carboxyllc acid.

Anal. Calc, for C₃₁H₂2O8·^5/δΗ2θ : C, 69.76; H, 4.39.

Found: C, 69.81, H, 4.46. θ EXAMPLE 70

JIRS. 3RS1-3-(2-Hydroxy-4-methoxyphenyl)-1-(3.4methvlenedloxvphenvll-5-(prop-l-yloxy)Indane.

a) (IRS.3RS1-3-f (2-Methoxvmethoxy)-4-methoxyphenyl)Ί-113,.4-methylenedlo«yphenyl) -5- (prop-l-yloxyllndaiue.

A solution of (IRS, 2SR, 3RS)-3-[2-(methoxymethoxy)-420 methoxyphenylJ-1-(3,4-methylenedioxyphenyl)-5-(prop-lyloxy) indane-2-carboxylic acid (0.2g, 0.39mmol) in dichloromethane (4ml) and pyridine (28μ1, 1.6 mmol) was cooled to 0 °C under argon. To this solution was added thionyl chloride (60 μΐ, 0.8 mmol). The mixture was 'n- 25 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 (4ml) and triethylamine (250μ1) added. To this solution at room temperature under argon was added 2-mercaptopyridine-Noxide (120 mg, 0.8mmol) dissolved in dichloromethane (lml). After stirring for 20 min at room termperature t-butylthiol (450μ1, 4mmol) 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 3-M-aq. HCl. The

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-71 organic extract was washed with water, sat. aq. NaHCO3 solution and finally brine. After drying (MgSC>4 anhydrous), the product was filtered and evaporated. Purification by column chromatography gave the title compound (0.075 g, 41%).

^XH NMR (CDC1₃) : δ 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).

b) IIRS.3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3.4methvlenediQMvphenvl)-5- (prop-l-yloxy)indane

To a solution of (IRS,3RS)-3-[(2-methoxymethoxy)-4methoxyphenyl))-1-(3,4-methylenedioxyphenyl)-5-(prop-lyloxy) indane (0.075 g, 0.16 mmol) in methanol (5 ml) was added 4-5 drops of 6M-HC1 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. NaHCO3 solution and finally brine. After drying (MgS04 anhydrous) filtration and evaporation gave the title compound (0.064 g, 94%).

*H NMR (CDCI3) : δ 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).

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- 72 MS (exact mass) Μ+ Found: 418.1782 (Δ = -0.2 mDa for Ο26«26θ5) ·

EXAMPLE 71

11RS.2RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3.45 methvlenedloxyphenyl)-5-(prop-l-yloxy)Indane

To a slurry of sodium hydride (5 mg, 0.21 mmol) in dimethyl formamide (0.5 ml) was added (lRS,3RS)-3-<2hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-510 (prop-l-yloxy)indane (0.058 g, 0.14 mmol) at ice-bath temperature under argon. After stirring for 15 min,

£) ethyl bromoacetate (50 pi, 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

HC1. The organic extract was washed with water, sat. aq. NaHCO3 solution and finally brine. After drying (MgS04 anhydrous) filtration and evaporation followed by chromatography gave (IRS,3RS)-3-(2-carboethoxymethoxy-4methoxyphenyl) -1- (3,4-methylenedioxyphenyl) -5- (prop-120 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 f 6M-aqueous HC1 and extracted with ethyl acetate. After evaporation the residue was crystallized from ethyl o 25 acetate/hexane to give the title compound (0.035 g,

93%) .

m.p. 177-178 °C.’

NMR (CDCI3) : δ 7.18 (d, 1H, J = 8.5 Hz), 6.87 (d,

1H, J = 8.4 Hz), 6.88-6.71 (4 H, 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 (Δ = ⁺0.6 mDa for C28H28O7) .

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-73EXAMPLES 72-84

The following compounds were prepared by the procedures given above.

(IRS, 2SR, 3SR)-l-(4-Methoxyphenyl)-3-(3,4,5trimethoxyphenyl)indane-2-carboxylic acid;

(IRS, 2SR, 3SR)-1-(4-Ethoxyphenyl)-3-(3-4methylenedioxyphenyl)indane-2-carboxylic acid;

(IRS, 2SR, 3SR)-5-Carboxy-l, 3-bis(3,4-methylenedioxyphenyl) indane-2-carboxylic acid;

(IRS, 2SR, 3SR)-3-(4-Methoxyphenyl)-1-(3,415 methylenedioxyphenyl)-5-(prop-2-enyloxy)indane-2carboxylic acid;

(IRS, 2SR, 3RS)-3-(2,4-Dimethoxyphenyl)-5hydroxy-1-(3,4-methylenedioxyphenyl)-indane-2-carboxylic acid;

(IRS, 2SR, 3SR)-3-[5-(2,3-Dihydro)benzfuranyl]-5-hydroxy-l-(3,4-methylenedioxyphenyl)indane-2-carboxylic acid;

(IRS, 2SR, 3RS)-5-Hydroxy-3-(3,4-methylenedioxyphenyl) -1-(2,4,6-trimethoxyphenyl)indane-2carboxylic acid;

(IRS, 2SR, 3SR)-1-(5- (2, 3-Dihydro) benzfuranyl)-1-(4-methoxyphenyl)indane-2-carboxylic acid;

(IRS, 2SR, 3RS)-1-[3,4-(1,2-Ethylenedioxy)35 phenyl]-3-(4-methoxyphenyl)lndane-2-carboxylic acid;_

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-74(1RS, 2SR, 3SR)-5-Hydroxy-3-(3, 4-methylenedioxyphenyl) -1- (4-methoxyphenyl)indane-2-carboxylic acid;

(IRS, 2SR, 3RS)-5-Hydroxy-3-(4-methoxyphenyl)1-(2-methoxy-4,5-methylenedioxyphenyl)indane-2carboxylic acid;

r (IRS, 2SR, 3SR)-1-(3,4-Methylenedioxyphenyl)10 3-(4-methoxyphenyl)-5-(propyl-l-yloxy)indane-2carboxylic acid;

(IRS, 2SR, 3RS)-5-Methoxy-3-(4-methoxyphenyl)1-(2-methoxy-4,5-methylenedioxyphenyl) indane-215 carboxylic acid.

EXAMELEL_&5

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.

c Inhalant Enrmulation

A compound of formula I, (1 mg to 100 mg) is

C' 25 aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.

Tablets/Ingredients Per Tablet

30	1.	Active ingredient (Cpd of Form. I)	40 mg
	2.	Corn Starch	20 mg
35	3.	Alginic acid	20 mg
	4.	Sodium alginate	20 mg
40	5.	Mg stearate	1.3 mg 2.3 mg

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APO 00 4 3 3

- 75 Step 1

Step 2

Step 3

Step 4

Step 5

Step 6

Procedure.for tablets;

Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.

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 converion to wet granules.

The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.

The wet granules are then dried in an oven at 140°F (60*0 until dry.

The dry granules are lubricated with ingredient No. 5.

The lubricated granules are compressed on a suitable tablet press.

Parenteral Formulation

A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate c amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water O 25 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.

Claims (11)

1. CLAIMS:

   -761. A compound of formula (I) wherein:

   Ri is -X(CH₂)_nAr or -X(CH₂)_nR_{8 or} σ

   ο ²⁵

   R₂ is hydrogen, Ar or (c);

   ?! is -X(CH₂)_nR₈;

   P₂ is -X(CH₂)_nRg, or -XRgY;

   R3 and R5 are independently hydrogen, Rn, OH, Ci_₈alkoxy, S(O)_qR_lb N(R₆)₂, Br, F, I, Cl, CF₃, NHCORg, -XR9-Y or -X(CH₂)_nR₈ wherein the methylene groups of -X(CH₂)_nR₈ may be unsubstituted or substituted by one or more -(CH₂)_nAr groups;

   R4 is hydrogen, Rn, OH, Ci_5alkoxy, S(O)qRn, N(R₆)₂, -X(Rn), Br, F, I, Cl or NHCORg wherein the Cj.^elkoxy may be unsubstituted or substituted by OH, methoxy or halogen;

   Rg is independently hydrogen or Ci_4alkyl; R7 is independently hydrogen, Ci_galkyl or (CH₂)_nAr;

   BAD original

   AP 0 0 0 4 3 3

   -77Rg is hydrogen, R_llr CO
2. 2H, ΡΟ₃Η₂, P(O)(OH)R₇ or tetrazole;

   Rg is Cj_], Oalkyl, ^c2-10^al,ceny^{1 or} phenyl all of which may be unsubstituted or substituted by one or more OH, N(Rg)₂/ COOH, halogen or XCi_5alkyl;

   Rjq is R
3. 3 or R4;

   Rll is C^-galkyl, C₂-8^alkenyl, C₂-8^alkynyl all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(Rg)₂ or halogen;

   X is (CH₂)_n, 0/ NRg or S(O)_q;

   Y is CH₃X(CH₂)_nAr;

   naphthyl, indolyl, pyridyl or 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 of substituted by one or more R3 or R4 groups;

   A is C=0, or [C(Rg)2]m/

   30 B is -CH₂- or -O-;

   Zi and Z₂ are independently hydrogen, Ci_8alkyl, C₂-8^alkenyl, C2-8^al^kyⁿyl» OH, C^-galkoxy, S(O)qC1_₈alkyl, N(R₆}₂, Br, F, I, Cl, NHCORg,

   -X(CH₂)_nR₃, phenyl, benzyl or C₃_gcycloalkyl wherein the

   35 Ci-salkyl, C₂-8^alkenyl or C2-8^alkyⁿyl ^maY be optionally substituted by COOH, OH, CO(CH2)_nCH₃, CO(CH₂)_nCH₂N(Rg)₂,

   BAD ORIGINAL g >*T»AP Ο Ο Ο 4 3 3

   -78Α2. A compound of claim 1 wherein Rj is X(CH2>n^Ar' dihydrobenzofuranyl, benzodioxanyl, cyclohexyl, or Cx_4alkyl; R2 is a moiety of formula (a) or (b), C1-.4alk.yl, indolyl or hydrogen; R3 and R5 are independently hydrogen, OH, Ci_5alkoxy, halogen, -OCi_4alkyl phenyl, RnCO2R7, Ci_4alkyl, N(Rg)2, NH(CO)CH3, -X(CH2)nRg, ^_XR9* pyridyl, phenyl or S(O)pCi_5alkyl; R4 is hydrogen, OH, Ci-salkoxy, halogen, C₁_₄alkyl, N(R₆)₂, NH(CO)CH₃ or S(0)_pCi_₅alkyl; Z_lt Z₂ and Z₃ are independently XRgY, benzyl, hydrogen, OH, Ci_₅alkoxy, -N(R₆)₂, S(0)qCx-ealkyl, NHCORg, X(CH₂)_nR₈ or halogen, or Ζχ and Z₂ together may be -0-A-0 on contiguous carbons; Ρχ and P₂ are independently hydrogen, CO₂H or tetrazole; Ar is a moiety of formula (a), or (b), phenyl, or pyridyl and X is (CH₂)_n or oxygen.

   BAD ORIGINAL

   AP Ο Ο Ο * 3 3

   -78or halogen; or Ζγ and Ζ₂ together may be -O-A-O- on contiguous carbons;

   Z3 is Zj or XRgY; 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 < · R₂ is not hydrogen when X is S(O)q,· • when the optional double bond is present there is only one R^q and there is no Ρρ • the compound of Formula I is not (IRS)-1,3diphenylindene-2-carboxylic acid; (cis,cis)(IRS,3SR)-1,3-diphenylindane-2-carboxylic acid; (IRS)-3-(3-Methyl-l-phenyl-(1H)-ind-2en-l-yl) propionic acid; (IRS)-2[1,3-diphenyl(1H)-ind-2-en-2-yl]ethanoic acid; 3 diphenyll-ethoxyindene-2-carboxylic acid; 1,2,3,triphenylindene; 1,3 diphenylindene; 1-(2,3' dimethyl-2-buten-l-yl)-1,3-diphenylindene;

   ζ'’ 1, 3-diphenyl-2-methylindene; 1,3-diphenyl-2methylindane; 1,3-diphenylindane; 5,6dimethoxy-1,3-diphenylindene; 1,3-bis (4,5dimethoxy-2-hydroxyphenyl)-5, 6dimethoxyindane; 1,3-bis (3,4 dimethoxyphenyl) -5,6-dimethoxyindane; 1,3-dipheny-2methoxyindene, 1,3-diphenyl-2-ethoxy indene,

   5-fluoro-2-methyl-indene-3- acetic acid.

   BAD ORIGINAL £ a ρ ο Ο ο 4 3 3

   - 79 3. A compound of claim 2 wherein R3 is hydrogen, -X(CH2)_nRg or R11CO2R7; R4 and R5 are independently hydrogen, OH, Cx-salkoxy, SCx_5alkyl, F, Br, Cj_3alkyl or NH2; Ζχ and Z3 are hydrogen and Z2 is

   5 hydrogen, OH, Cj_5alkoxy, halogen, X(CH2)_nRQ, NH2, benzyl or NH(CO)CH3, or Ζχ and Z2 together may be O-A-O on contiguous carbons.
4. 4. A compound of claim 3 wherein Rj is a

   10 moiety of formula (b) and R2 is a moiety of formula (a) or (b); A is CH2, B is -O-; there is no optional double bond; Rx and XR2 are trans to Ρχ; Z2 is OH, C|_5alkoxy, -OCH2CHCH2 or hydrogen, Ζχ is hydrogen; R3 is hydrogen, X(CH2)qCO2H or CH=CHCO2H, R4 is hydrogen, substituted

   15 phenyl, or Cx_2alkoxy; and R5, Rxq and P2 are hydrogen.
5. 5. A compound of claim 1 selected from the group consisting of:

   20 (IRS, 2SR, 3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-carboxylic acid;

   -C (IRS, 2RS, 3SR) -5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)indane-2-carboxylic acid;

   O 25 (IRS, 2RS, 3SR)-5-Methoxy-3-(4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)indane-2-carboxylic acid;

   (IRS, 2SR, 3SR)-1,3-Bis(3,4-methylenedioxyphenyl)-530 5-hydroxyindane-2-carboxylic acid;

   (IRS, 2SR, 3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-ΙΟ, 4-methylenedioxyphenyl)-5-(prop-l-yloxy)-indane-2carboxylic acid;

   BAD ORIGINAL £

   AP Ο Ο Ο 4 3 3

   -80(IRS, 2SR, 3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-ΙΟ, 4-methylenedioxyphenyl)-5-(prop-l-yloxy)-indane-2carboxylic acid;

   5 (IRS, 2SR, 3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1(2-methoxy-4,5-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid;

   (IRS, 2SR, 3RS)-3-[2-(l-Carboxyeth-2-yloxy)-4-methoxy10 phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid, bis-dicyclohexylamine salt;

   Q (IRS, 2SR, 3SR)-3-(2-( (E)-2-Carboxyethen-l-yl]-4methoxyphenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-115 yloxy)indane-2-carboxylic acid;

   (IRS, 2SR, 3SR)-3-(2-(2-Carboxyeth-l-yl)-4-methoxyphenyl] -1-(3, 4-methylenedioxyphenyl)-5-(prop-l-yloxy)indane-2-carboxylic acid;

   (IRS, 2SR, 3RS)-3-(2-(3-Carboxyphenyl) -4-methoxyphenyl]-1(3, 4-methylenedioxyphenyl)-5- (prop-l-yloxy)indane-2carboxylic acid-.

   o

   25
6. 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier.
7. 7. A compound according to any one of claims

   30 1 to 5 for use as an active therapeutic substance.
8. 8. A compound according to any one of claims 1 to 5 for use in antagonizing endothelin receptors.

   BAD ORIGINAL &

   AP Ο 00 4 33
9. 9. A compound according to any one of claims 1 to 5 for use in treating hypertension, renal failure or cerebrovascular disease.

   5 10. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament to use in the treatment of hypertension, renal failure or cerebrovascular disease.

   11. 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 according to any one of claims 1 to 5.

   12. A process for the preparation of a compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II) wherein Ζχ, Z₂, Z3 and are as described in claim 1 or a group convertable thereto, and X is alkyl, with an organomagnesium compound of formula (III)

   R₂-(CH₂)_n-MgBr (III) wherein R₂ is as described in claim 1 or a group 35 convertable thereto, in a suitable solvent to provide a compound of formula (IV)

   BAD ORIGINAL ft (IV)

   AP Ο Ο 0 4 3 3 which is reduced and thereafter, when desired or necessary undergoes,
10. 10 a) insertion of R^q (when other than hydrogen) through conjugate additon; and/or

    b) alkylation or acylation to give compounds wherein Ρχ and P₂ are other than CO₂H; and/or

    c) conversion R^, R₂, Ζχ, Z₂ and Z3.
11. 15 to afford a compound of formula (I).