Antagonists endothelioma receptors, farmcampsite, the retrieval method, the method of suppressing endothelioma receptors

 

(57) Abstract:

This paper describes a new indan and inden derivatives, which are endothelium receptor antagonists of formula (I)

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R1=-X(CH2nAr or-X - (CH2)nCO2H (tetrazol);

R2- Ar;

P1and P2-X - (CH2nCO2H or-X - (CH2ntetrazol;

Z1, Z2, Z3IS H, OH, CH1-8-alkoxy, N(R6)2, NHCOR6, phenyl, benzyl;

R6- H or lower alkyl.

The described method of obtaining the relevant interaction of ester and magyarkanizsa connection, and describes farmcampsite and a method of suppressing endothelioma receptors. 4 C. and 6 C.p. f-crystals, 1 table.

This invention relates to new indan and inden derivatives, pharmaceutical compositions containing these compounds, and their use as endothelina receptor antagonists.

Endothelin (ET) is an extremely high level vasoconstrictor peptide synthesized and selected vascular endothelium. Endothelin exists as three isoforms, ET-I, ET-2 and ET-3. It was found that of these, only ET-1 and ET-3 are expressed in systems mlekopitayushchie which provides a profound impact on the cardiovascular system, in particular, coronary, renal and cerebral circulation. Increased or abnormal secretion of endothelin is associated with the contraction of smooth muscles, which are involved in the pathogenesis of cardiovascular and cerebral-vascular, respiratory and renal pathophysiologie. It was reported about the existence of elevated levels of endothelin in plasma in patients with significant hypertension, acute myocardial infarction subarachnoid blood circulation, atherosclerosis, and patients with uremia undergoing dialysis.

In vivo, endothelin exerts marked effects on blood pressure and cardiac output. Vnutristenocna injection test dose of ET (from 0.1 to 3.0 nmol/kg) causes rats temporary, associated with dose depressor response (response) (later, from 0.5 to 2 min) with subsequent sustained, dose-dependent increase in arterial blood pressure, which can be increased within 2-3 h after dose. In rats, doses of more than 3 nmol/kg often causes the aircraft to the outcome.

Endothelin apparently has a preferable effect on the renal vascular bed. It causes significant prolonged decline in renal blood flow, accompanied the first antinatriuretic effect despite a significant increase trialing natriuretic peptide. Endothelin stimulates renin activity (plasma). These results suggest that ET is involved in the regulation of renal function and call in a whole range of renal disorders, including acute renal failure, cyclosporine nephrotoxicity and chronic renal insufficiency.

Studies have shown that in vivo cerebral vascular network is highly sensitive to both vasodilator and vasoconstrictor effects of endothelin. So ET can be an important mediator of cerebral vasospasm is a frequent and often fatal consequences of subarachnoid hemorrhage.

ET also has a direct effect on the Central nervous system, such as a severe apnea and ischemic disorders, which suggests that ET may participate in the development of cerebral infarction and neuronal death.

ET can also be involved in myocardial ischemia (Nichols et al. Br. J. Pharm. 99: 597-601, 1989, and Clozel, Circ. Res., 65: 1193-1200, 1989), spasms of the coronary vessels (Fukuda et al., Eur. J. Pharm. 165: 301-304, 1989 and Liischer, Circ., 83:701, 1991) in heart failure, the proliferation vascular et al., Biochem. & Biophys. Res. Commun. 158: 880-881, 1989, and Lerman et al., New Eng. J. of Med. 325: 997-1001, 1991). It was shown the existence of elevated levels of endothelin after coronary plastic surgery with the use of an inflatable balloon (Kadel et al., No 2491, Circ. 82:627, 1990).

In addition, it was found that endothelin is a potent constrictor isolated from mammalian tissue of the respiratory tract, including human bronchi. (Ushida et al., Eur. J. of Pharm. 154: 227-228 1988, La Gente, Clin. Exp. Allergy, 20: 343-348, 1990; and Springall et al., Lancet, 337: 697-701, 1991).

Endothelin is associated with the occurrence of hemorrhage and necrotic disorders of the gastric mucosa (Whittle et al., Br. J. Pharm. 95: 1011-1013, 1988); symptom Raynand'a, Cinniniello et al., 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: 262 to 264, 1991, cyclosporin-induced renal failure or hypertension (Eur. J. Pharmacol., 180: 191-192, 1990, Kidney Int., 37: 1487-1491, 1990) and bacterial endotoxin-toxic shock and other caused by endotoxin diseases (Biochem., Biophys. Res. Commun. 161: 1220-1227, 1989, Acta Phisiol Scand. 137: 317-318, 1989), J. Clin. Invest., 83, 1989, 1762-1767.

Thus, endothelioma receptor antagonists will provide a unique method for therapy of hypertension, renal insufficient is osclerosis, symptom Raynand'a, ulcers, sepsis, migraine, glaucoma, endotoxin shock caused by endotoxin multiple organic disorders or widespread intravascular coagulation, cyclosporin-induced renal failure and as an adjunct with plastic surgery on the blood vessels and prevent restenosis.

The invention includes indan - and EnterpriseOne represented by the formula (I), and pharmaceutical compositions containing these compounds, and their use as endothelin receptor antagonists, which are useful in treating a variety of cardiovascular and renal diseases, including, but not limited by them of the following: hypertension, acute and chronic renal failure, cyclosporine-induced nephrotoxicity, sudden attack, cerebrovascular vasospasm, myocardial ischemia, angina, heart failure and atherosclerosis.

In addition, the invention provides a method of suppressing endothelioma receptors in animals, including humans, which includes an introduction to the needy in this animal an effective amount of compounds of formula (I).

The compounds of this image is/SUB>)nR8or (c)

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R2is hydrogen, Ar or (c);

R1- -X - (CH2)nR8;

R2- -X - (CH2)nR8or-XR9Y;

R3and R5independently hydrogen, R11, OH, C1-8-alkoxy, S(O)qR11; N(R6)2, Br, F, I, Cl, CF3, NHCOR6, -R11CO2R7, -XR9-4or-X - (CH2)nR8where the methylene group-X - (CH2)nR8can be unsubstituted or substituted by one or more -(CH2)nAr groups;

R4is hydrogen, R11, OH, C1-5-alkoxy, S(O)qR11N(R6)2, -X(R11), Br, F, I, Cl, or NHCOR6where C1-C5the alkoxy may be unsubstituted or substituted with OH, methoxy or halogen;

R6independently is hydrogen or C1-4-alkyl;

R7independently is hydrogen, C1-C6-alkyl or (CH2)nAr;

R8is hydrogen, R11CO2R7, PO3H2, P(O)(OH)R7CN, -C(O)N(R6)2tetrazol or or6;

R9- C1-C10-alkyl, C2-C10alkenyl or phenyl, all of which can be unsubstituted or substituted by one or more OH, N(R6)2, COOH, halogen, and the sludge, C2-C8alkenyl, C2-C8-quinil, they can all be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2or halogen;

X (CH2)n, O, NR6or S(O)q;

Y - CH3or X(CH2)nAr;

Ar is

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naphthyl, indanyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, diazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinil, pyrrolyl or pyrimidyl; they can all be unsubstituted or substituted by one or more R3or R4groups;

A is C = O or [C(R6)2]m;

B is-CH2- or-O-;

Z1and Z2independently is hydrogen, C1-C8-alkyl, C2-8alkenyl, C2-8-quinil, OH, C1-8-alkoxy, S(O)qC1-8-alkyl, N(R6)2, Br, F, I, Cl, NHCOR6, -X - (CH2)nR8, phenyl, benzyl or C3-6-cycloalkyl, where C1-8-alkyl, C2-8alkenyl, or C2-8-quinil may be independently substituted by COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2or halogen, or Z1and Z2the q = 0, 1 or 2;

n = 0 - 6, an integer;

m = 1, 2, or 3;

the dotted line indicates the optional presence of a double bond,

or their pharmaceutically acceptable salt, provided that R2is not hydrogen when X is - S(O)q; when the optional double bond is present, there is only one R10and there is no R1; a compound of formula I is not (1RS)-1,3-diphenylethan-2-carboxylic acid; (CIS,CIS)-(1RS,3SR)- 1,3-diphenylethan-2-carboxylic acid; (1RS)-3-[3-methyl-1-phenyl- (1H)-ind-2-EN-1-]Il propionic acid; or (1RS)-2[1,3-diphenyl-(1H)- ind-2-EN-2-yl]ethanoic acid. The invention also includes a pharmaceutical acceptable salt complexes.

All the alkyl, alkenyl, quinil and alkoxy groups can be straight or branched. The term "halogen" is used for education designations iodo, fluorescent, chloro or bromo. Alkyl groups can be substituted by one or more halogen to complete halogenation.

The compounds of this invention can contain one or more asymmetric carbon atoms and may exist in racemic or optically active form. All these connections and diastereoisomer considered as included in the scope of this isobases : X(CH2)nAr (Ar is (a) or (b)), dihydrobenzofuranyl, benzodioxane, cyclohexyl, C1-4-alkyl, R2represents (a), (b) C1-4-alkyl, indanyl or hydrogen; R3and R5are independently hydrogen, OH, C1-5alkoxy, halogen, -OC1-4-alkyl phenyl, R11CO2R7C1-4-alkyl, N(R6)2, NH(CO)CH3, -X - (CH2)nR8, -XR9pyridyl, phenyl or S(O)pC1-5-alkyl; R4represents hydrogen, OH, C1-5-alkoxy, halogen, C1-4-alkyl, N(R6)2H(CO)CH3or S(O)pC1-5-alkyl; Z1, Z2and Z3independently represent XR9Y, benzyl, hydrogen, OH, C1-5-alkoxy, -N(R)6)2, S(O)qC1-8-alkyl, NHCOR6X(CH2)nR8or halogen, or Z1and Z2together may be-O-A-O on adjacent carbon atoms; R1and R2independently represent hydrogen, CO2H or tetrazol, Ar is (a), (b), phenyl, or pyridyl; X represents (CH2)nor oxygen.

More preferred are compounds in which R3represents hydrogen or-X - (CH2)nR8, R11CO2R7; R4and R5independent SUB> are hydrogen and Z2represents hydrogen, OH, C1-5alkoxy, halogen, X(CH2)nR8, NH2, benzyl, NH(CO)CH3or Z1and Z2together can be O-A-o

Most preferred are compounds in which R1is (b) and R2represents (a) or (b); A is CH2B is-O-; there is no optional double bond; R1and R2are TRANS with respect to R1; Z2is OH, C1-5-alkoxy, -OCH2CHCH2or hydrogen, Z1represents hydrogen; X(CH2)qCOOH or CH=CHCO2H, R4represents hydrogen, substituted phenyl, or C1-2-alkoxy and R5, R10and R2- hydrogen.

Especially preferred are the following compounds:

(1RS), 2SR, 3SR)-1-(4-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid;

(1RS, 2RS, 3SR)-5-hydroxy-3-(4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)indan-2-carboxylic acid;

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

(1RS, 2SR, 3SR)-1,3-bis(3,4-methylenedioxyphenyl)-5-5 - hydroxyine-2-carboxylic acid;

(1RS, 2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1- (3,4-methylendioxy the 4,5-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid;

(1RS, 2SR, 3RS)-3-2-(1-carboxylat-2-yloxy)-4-methoxyphenyl-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid, salt of bis-dicyclohexylamine;

(1RS, 2SR, 3SR)-3-[2-[(E)-2-carboxylate-1-yl-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid;

(1RS, 2SR, 3SR)-3-[2-(2-carboxylat-1-yl)-4-methoxyphenyl] -1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 carboxylic acid;

(1RS,2SR,3RS)-3-[2-(3-carboxyphenyl)-4-methoxyphenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid;

This invention provides compounds of formula (I) above

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which can be prepared according to the method, including

(a) the effect of the compounds of formula (2)

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where X is C1-5-alkyl with substituted benzaldehyde or aldehyde of formula (3)

D - CHO

where D is Ar or (c), as defined in the formula I, in a suitable solvent such as benzene with a catalyst such as piperidine acetate when heated to the boil under reflux order to obtain the compounds of formula (4)

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Cyclization of compound (4) in the presence of a suitable Lewis acid such as titanium tetrachloride or aluminum chloride, or otherwise, when Z1is a 3-OR (meth>Dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an appropriate solvent or otherwise bromination of pyridine hydrobromide by perbromide in dichloromethane followed by treatment of 1,5-diazabicyclo(4.3.0) non-5-Yong gives indanone formula (6)

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(b) or otherwise, the compound of formula 6, where Z1, Z2and Z3are hydrogen and

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can be prepared by treatment of 2 bromobenzoic acid with two equivalents of n-utility in a solvent such as tetrahydrofuran in an argon atmosphere at -78oC followed by the addition of the carboxylic acid of the formula (7)

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that gives compound of formula (8)

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Treatment of compounds of type (8) thionyl chloride when heated to the boil under reflux gives the acid chloride of the acid that can be isolated by concentration under reduced pressure. This acid chloride of the acid can then be treated diethyl magnesium by malonate in a solvent such as diethyl ether, to obtain the compounds of formula (9)

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The reaction of compounds of type (9) when heated to the boil under reflux with 5% aqueous sodium carbonate gives the compounds of formula (10)

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c) Processing indanone formula (11)

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where Z
R2(CH2)nMgBr,

in which R2such as defined for formula I, or a group convertible to him, in a suitable solvent at 0oC:

gives the compounds of formula (13)

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Saponification of compounds of formula (13) by use of sodium hydroxide in aqueous methanol, followed by reduction with triethylsilane and boron TRIFLUORIDE-efratom in a suitable solvent, such as dichloromethane, at 0oC leads to racemic compounds of formula (14)

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Conjugated addition of nucleophiles to the ether, obtained from formula (14), followed by saponification leads to compounds of formula (I) with R10other than hydrogen. Re-instatement of a double bond in the ester derived from such acids with subsequent conjugated accession, and other nucleophilic particles and subsequent saponification gives the compounds of formula (I) in which one of R10of the substituents is not hydrogen.

The recovery of the compounds of the formula (13) triethylsilane and boron TRIFLUORIDE-efratom in a suitable solvent, such as dichloromethane, at 0oC with subsequent hydrogenation with gaseous hydrogen under a pressure of approximately 60 psi (4.22 kg/cm2)

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Alkylation or acylation of essential enolate derived from formula (15) gives compounds where P1and P2are as defined for formula (I).

Otherwise, the hydrogenation of compounds of formula (13) with gaseous hydrogen under a pressure of approximately 60 psi in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable solvent, such as ethyl acetate or methanol containing 1-5% acetic acid gives the compounds of formula (15). Treatment of these compounds with a base, such as sodium hydroxide in a suitable solvent such as aqueous ethanol gives the racemic compounds of the formula (16)

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where Z1, Z2and Z3are hydrogen;

R1= R2;

n = 0.

Treatment of compounds of formula (13) triethylsilane and boron TRIFLUORIDE-efratom in a suitable solvent, such as dichloromethane, at 0oC with subsequent interaction with samarium II iodide in a suitable solvent, such as tetrahydrofuran, and then the saponification gives the compounds of formula (17)

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With the appropriate adjustments and protection of any chemical functional groups synthesis of the remaining compounds of formula (I) is CLASS="ptx2">

The purpose of using the compounds of formula (I) or its pharmaceutically acceptable salts for the treatment of humans and other mammals it is usually made in accordance with standard pharmaceutical practice as a pharmaceutical composition.

For treatment of these diseases, the compounds of formula (I) and their pharmaceutically acceptable salts can be administered in a standard way, for example oral, parenteral, sublingual, dermal, rectal, by inhalation or transbuccal method.

The compounds of formula (I) and their pharmaceutically acceptable salts which are active when introduced orally can be formulated as syrups, tablets, capsules and pellets. Technology of preparation of a medicinal product in the form of a syrup usually should include a suspension or solution of the compound or its salt in a liquid carrier, such as ethanol, peanut oil, olive oil, glycerine or water with aromatic additives and dyes. When the composition is prepared in tablet form, can be used any pharmaceutical carriers commonly used in the technology of preparation of solid dosage drugs. Examples of such carriers include magnesium stearate, ter is used in the form of capsules, suitable are any common inclusion in the capsule, for example using the aforementioned carriers in the hard gelatin shell of the capsule. When the composition is prepared in the form of a capsule, soft gelatin shell, can be used for any pharmaceutical carriers customarily used for preparing dispersions or suspensions, for example aqueous gums, cellulose, silicates or oils, and are enclosed in a soft gelatin shell capsule.

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

Typical compositions for inhalation are made 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 trichlorotrifluoromethane.

A typical composition of the suppository comprises a compound of formula (I) or its pharmaceutically acceptable salt, which is active in the introduction of this way, with svyazyvayus wax or fats or their synthetic analogues.

Typical transdermal formulations include conventional aqueous or anhydrous fillers, such as paste, ointment, lotion, or cream, or used in the form of medical patches, plaques, or films.

Preferably the compositions are manufactured in standardized dosage form such as tablets, capsules or measured aerosol dose so that the patient can apply them in a single dose.

Each dosage unit for oral administration contains respectively from 0.1 to 500.0 mg/kg, and preferably from 1 to 100 mg/kg, and each dosage unit for parenteral administration contains respectively from 0.1 to 100.0 mg, of the compounds of formula (I) or its pharmaceutically acceptable salt, calculated on the free acid. Each dosage unit for insertion through the nose contain respectively 1 to 400 mg, preferably from 10 to 200 mg per individual. The compositions of local application contain from 0.01 to 1.0% of the compound of formula (I).

The daily dosage required for oral administration, respectively approximately from 0.01 to 40.0 mg/kg, the compounds of formula (I) or its pharmaceutically acceptable salt in the calculation of the free acid. Daily dosage, Tribunali (I) or its pharmaceutically acceptable salt in the calculation of the free acid.

The daily dosage required for insertion through the nasal or oral inhalation, respectively from about 10 to 500 mg/individual. The active ingredient may be administered 1 to 6 times a day, which is sufficient for the manifestation of the desired activity.

With the introduction of the compounds of this invention in accordance with this invention excludes undesired Toxicological effects.

The biological activity of the compounds of formula (I) is demonstrated by the following tests.

1. Test link

A) Preparation of membranes.

Rat cerebellar or cortical layer of the kidneys were rapidly removed and immediately frozen in liquid nitrogen or used fresh. Fabric, 1 to 2 g for cerebellar or 3 - 5 g for the cortical layer of the kidney, homogenized in 15 ml of buffer containing 20 mm Tris HCl, 5 mm EDTA, pH 7.5 at 4oC, using a mechanical homogenizer. The homogenates were filtered through cheesecloth and centrifuged at 20000 g (rpm) for 10 min at 4oC. the Supernatant was removed and centrifuged at 40,000 g for 30 min at 4oC. the resulting precipitate resuspendable in a small volume of buffer containing 50 mm Tris, 10 mm Mg Cl2, pH 7.5; divided on aliquo the number of protein in the analysis of binding was 1 and 5 mg for cerebellar and cortical layer of the kidney.

Freshly isolated mesenteric artery and collateral vascular bed of the rat was washed in ice-cold saline and removed lymph nodes along the main vessel. Then the tissue is homogenized using Polytron in buffer containing 20 mm Tris and 5 mm EDTA, pH 7.5 at 4oC in 15 ml volume 6 gm mesenteric bed artery. The homogenate was missed through cheesecloth and centrifuged at 2000 g for 10 min at 4oC. the Supernatant was removed and centrifuged at 40,000 g for 30 min at 4oC. the precipitate resuspendable as explained above for cerebellar and cortical layer of the kidney. In experiments on the binding used approximately 10 mg of membrane protein for each tube.

C) Protocol125I ET - I binding.

Binding125I ET - I with membranes of rat cerebellum (2 to 5 mg protein/tube) or the cortical layer of the kidney (3 to 8 mg of protein per tube) were measured after 60 minutes incubation at 30oC in a buffer of 50 mm Tris HCl, 10 mm MgCl2, 0.05% (BSA) bovine serum albumin, pH 7.5 in a total volume of 100 ml of Membrane protein was added to tubes containing buffer), or the indicated concentration of compounds. [125I] ET-I (2200 Ci/mmol) diluted in the same buffer containing bovine whom the statements were measured in the absence and presence of 100 nm unlabeled ET-I. After incubation, the reaction was suppressed 3 ml of chilled buffer containing 50 mm Tris and 10 mm Mg Cl2, pH 7.5. Associated with membranes radioactivity was separated from free ligand by filtration through filter paper Whatman GF/C and washing of the filters 5 times in 3 ml of chilled buffer, using the device to collect cells Brandel'a. The filters counted in a gamma counter with an efficiency of 75%. IC50'S for the compounds of the present invention is in the range from 0.1 nm to 50.0 μm.

11. The activity of vascular smooth muscle in vitro

The rat aorta was cleaned of connective tissue and adhering fat and cut into ring segments of approximately 3 to 4 mm long. Vascular rings suspended in the cells for incubation bodies (10 ml) containing bicarbonate Krebs solution of the following composition, mm: NaCl-112,0; RCl-4,7; KH2PO4-1,2; MgSO4-1,2; CaCl2A-2.5; N2HCO3-25,0 and dextrose is 11.0. The incubation solutions were maintained at 37oC and continuously aeronavali a mixture of 95% O2and 5% CO2. The residual voltage of the aorta maintained at 1 g and allowed to be balanced within 2 h, during which time the incubation solution was replaced every 15 - 20 minutes of Isometric tension were recorded on demolatorul reduction built by the method of gradual step-by-step addition of a stimulant. The concentration of ET-I was increased only after the previous concentration was given in response to a steady decline. On each piece of tissue received only one curve concentration-response to ET-I. receptor Antagonists ET was added to the paired tissue samples for 30 min prior to the determination of the concentration curves of the response to stimulants reduction.

Induced ET-I reduction vessels expressed as a percentage of the response to 60 mm KCl for each individual tissue, which is determined at the beginning of each experiment. Data expressed as mean standard error of the mean (S. E. M.). Condensates dissociation (Kb) competitive antagonists was determined by the standard method of Arunlakshana u Schild'a. The valid range for compounds of the present invention is in the range from 0.1 nm to 50.0 μm.

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

Example 1.

(1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylic acid.

a) Ethyl(1RS)[1-Hydroxy-1-(4-methoxyphenyl)]-3-vinylidene-2 - carboxylate.

To dry the magnesium shavings (0.88 g, 36 mmol) in an argon atmosphere was added in portions a solution of p-bromoanisole (4.5 ml, 36 mmol) in 5% THF/Et2O (37 ml). On the g, 18 mmol) in Et2O (300 ml) in an argon atmosphere at 0oC. the resulting mixture allowed to warm to room temperature and was stirred 10 minutes and the Mixture was distributed between 3M HCl (100 ml) and EtOAc (200 ml). The organic extract was successively washed with water, aqueous NaHCO3H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed under reduced pressure to obtain a yellow oil, which was treated with Et2O/hexane. The formed solid product was collected by filtration (3.47 g). The filtrate was concentrated under reduced pressure and purified instant chromatography. The material that was isolated, processed Et2O/hexane, and the resulting additional solid product (1.76 g, 75% yield) was collected by filtration to obtain named in the title compound.

C) ethyl (RS)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylate.

To a solution of ethyl (1RS) [1-hydroxy-1-(4-methoxyphenyl)]-3 - phenylindane-2 carboxylate (4,65 g, 12,0 mmole) in CH2Cl2(40 ml) at 0oC in argon atmosphere was added triethylsilane (2.34 ml, 14.6 mmol), and subsequently, boron TRIFLUORIDE, everet (8.8 ml, 71 mmol). The reaction mixture is allowed to warm to room temperature and was stirred 10 min, mo washed with water, water N2HCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure and the residue was purified instant chromatography on silica gel, elwira 10% EtOAc/hexane to obtain named the title compound (4.2 g, 95%) as a mixture of 1 and 2 isomers of the double bond.

(C) Ethyl (1RS,2SR,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2 - carboxylate.

To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-phenylindane-2 - carboxylate (5.75 g, 15 mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg). The resulting suspension was stirred in an atmosphere of H21 day, then was filtered through a layer of Celite. The filtrate was concentrated under reduced pressure, which gave named in the title compound, which was used without further purification.

d) (1RS,2RS,3-SR)-1-(4-Methoxyphenyl)-3-phenylindane-2 - carboxylic acid.

To a solution of ethyl (1RS, 2SR, 2SR)-1-(4-methoxyphenyl)-3-phenylindane-2-carboxylate, (5.5 g, 14.8 mmole) in EtOH (70 ml) was added 5H NaOH (9 ml, 45 mmol). The resulting mixture was stirred in an argon atmosphere for 1 day, added during this time H2O (70 ml). The mixture was concentrated under reduced pressure. The aqueous residue was extracted with Et2O and Et2O extracts were discarded. Water is an ode and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure to obtain an oily residue crystallized upon standing. The solid product was precrystallization from EtOAc/hexane, having named the title compound (4.25 g, 83%); So pl. 164 - 166oC.

Here and below:

in the spectrum of TMR1H-NMR m - multiplet, d - doublet, s - singlet, t - triplet, dd = double doublet, br - broadened, apparent - apparent, sextet - sextet, dt (double triplet,

In the data element. analysis: Calc. - designed, Found - found

In these mass-spectrometry: (exact mass) exact mass

1H NMP (CDCl3): 7.35 - 7.18 (m, 9H); 6,92 - 6.88 (m, 4H), and 4.68 (d, 1H, J = 10 HZ); with 4.64 (d, 1H, J = 10 HZ); 3.81 (S, 3H); 3.34 (t, 1H, J = 10 HZ).

M: 345(M + H)+].

Anal. CaIc. C23H20O3: C, 80.21; H, 5.85.

C, 80,21; H 6,03.

Example 2. (TRANS, TRANS)-1,3-di(4-Methoxyphenyl)-indan-2 - carboxylic acid.

a) Ethyl-2-Benzoyl-3-(4-hydroxyphenyl)propionate.

To a solution of 4-hydroxybenzaldehyde (31.7 g, 0.26 mmol) and ethyl benzoylacetate (45.5 ml, 0.26 mmol) in EtOH (45 ml) in an argon atmosphere was added piperidine (2.6 ml, 0.026 mmol) and acetic acid (3 drops). After stirring overnight at room temperature, the resulting solid mixture amrabat is Noah in the title compound (61.0 g, 79%).

b) Ethyl (2RS,3SR)-3-(4-Hydroxyphenyl)-1-oxonian-2 - carboxylate.

To a mixture of ethyl 2-benzoyl-3-(4-hydroxyphenyl)propionate (0.50 g, 1.7 mmol) in CH2Cl2(15 ml) at 0oC in argon atmosphere was added titanium tetrachloride (0,93 ml, 8.3 mmol). The resulting mixture allowed to mix overnight at room temperature. The slow reaction was stopped by adding 3M chilled HCl, and then the reaction mixture was distributed between EtOAc (50 ml) and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed under reduced pressure and the solid residue was recrystallize from EtOAc/hexane to obtain named the title compound (410 mg, 82%).

c) Ethyl (2RS, 3SR)-3-(4-Butyldimethylsiloxy)-1-oxonian-2-carboxylate.

To a solution of ethyl (2RS,3SR)-3-(4-hydroxyphenyl)-1-oxonian-2 - carboxylate (3.0 g, 10.2 mmol) in DMF (10 ml) in an atmosphere of argon was added imidazole (1.72 g, 25.3 mmol) and t-butyldimethylsilyl-silane (1.82 g, 12.1 mmol). The resulting mixture allowed to mix for 3 days at room temperature, then poured into dilute aqueous HCl and was extracted with EtOAc (2x). United organizedbeautiful removed under reduced pressure to obtain named in the title compounds (of 5.40 g), which was used without further purification.

d) Ethyl 3-(4-t-butyldimethylsiloxy)-1-oxenden-2-carboxylate.

To a solution of ethyl (2RS,3SR)-3-(4-t-butyldimethylsiloxy)-1 - oxonian-2-carboxylate (130 mg, 0.32 mmol) in CH2Cl2(3 ml) in an argon atmosphere was added 2,3-sodium dichloro-5,6-dicyano-1,4 - benzoquinone (80 mg, 0.35 mmole). The resulting mixture was stirred for 2.5 hours. Added aqueous NaHSO3and EtOAc, and the mixture was stirred 5 minutes the Aqueous phase was separated and was extracted with EtOAc, and the combined organic extracts were washed successively aqueous NaHCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure and the residue was purified instant chromatography on silica gel with the aim of obtaining mentioned in the title compound (110 mg, 85%).

e) Ethyl (1RS)-3-(4-t-butyldimethylsiloxy)-1-hydroxy-1- (4-methoxyphenyl)inden-2-carboxylate.

To dry the magnesium shavings (119 mg, 4.9 mmol) in an argon atmosphere portions solution was added p-bromoanisole (and 0.61 ml, 4.9 mmol) in 9:1 Et2O/THF (10 ml). The resulting solution of p-methoxyphenyl magnesium bromide was added to a solution of ethyl 3-(4-t-butyldimethylsiloxy)-1-oxenden-2-carboxylate (1.00 g, 2.5 mmol) in Et2O (60 ml) in the atmosphere and the camping was distributed between 3M HCl and EtOAc. The organic extract was washed successively H2O, aqueous NaHCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure to obtain the title compound (1.47 g), which was used without further purification.

f) the Ethyl (RS)-1-(4-t-butyldimethylsiloxy)-3- (4-methoxyphenyl)inden-2-carboxylate.

To a solution of ethyl (1RS)-3-(4-t-butyldimethylsiloxy)-1-hydroxy-1-(4-methoxyphenyl)inden-2-carboxylate (2.5 mmol, prepared above) in CH2Cl2(10 ml) at 0oC in argon atmosphere was added triethylsilane (0.48 ml, 3.0 mmol), and subsequently, boron TRIFLUORIDE, everet (1.8 ml, 14.6 mmol). The reaction mixture is allowed to warm to room temperature and was stirred for 10 minutes, adding slowly during this time of 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively H2O, aqueous NaHCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure and the residue was purified instant chromatography on silica gel, elwira 15% Et2O/hexane to obtain named in the title compounds as a mixture of 1 and 2 isomers of the double bond (820 mg, 67% for two steps).

g) Ethyl (1RS, 2SR,3SR)-1-(4-t-tersilochinae)-1- (4-methoxyphenyl)inden-2-carboxylate (a mixture of 1 and 2 isomers of double bonds) (750 ml) 1.5 mmole) in EtOH (25 ml) was added 5% palladium on activated carbon (70 mg). The resulting suspension was stirred in an atmosphere of H218 hours, then was filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to obtain named the title compound (730 mg, 97%) which was used without further purification.

h) Ethyl (1RS,2RS,3SR)-1-(4-hydroxyphenyl)-3-(4-methoxyphenyl) indan-2-carboxylate.

To a solution of ethyl (2RS,2SR,3SR)-1-(4-butyldimethylsiloxy) -3-(4-methoxyphenyl)indan-2-carboxylate (723 mg, 1.4 mmol) in EtOH (20 ml) was added 1M NaOH (1.6 ml, 1.6 mmole) and the resulting mixture was stirred at room temperature for 30 minutes the Mixture was distributed between 3M HCl and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed successively H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure to obtain named the title compound (554 mg, 100%).

(i) Ethyl (CIS,CIS)-1,3-di(4-methoxyphenyl)indan-2-carboxylate.

To a solution of ethyl (1RS, 2RS, 3SR)-1-(4-hydroxyphenyl)-3-(4 - methoxyphenyl)indan-2-carboxylate (270 mg, 0.7 mmol) in acetonitrile (5 ml) at 0oC added 1.8-diazabicyclo (5.4.0)-undec-7-ene (0.25 ml, 1.7 mmol), and VPO and all night. The mixture was distributed between EtOAc and dilute aqueous HCl. The organic extract was washed with saturated aqueous NaCl and dried. The solvent was removed under reduced pressure, and the residue was purified immediately by chromatography to obtain named the title compound (40 mg, 32% relative to the selected source material).

j) (TRANS,TRANS)-1,3-Di(4-methoxyphenyl)inden-2-carboxylic acid.

To a solution of ethyl (CIS,CIS)-1,3-di(4-methoxyphenyl)-indan-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 allowed to mix at room temperature overnight. Thin-layer chromatographic analysis at this time showed that the reaction was completed, after which was added 5M BaOH (0.15 ml, 0.75 mmol) and the mixture is left to stand for 5 days at 0oC. was Added water and the mixture was concentrated under reduced pressure. The aqueous residue was extracted with Et2O (2x) and threw essences. The aqueous phase was acidified using 6M HCl and was extracted with EtOAc several times. The combined EtOAc extracts were washed successively H2O and saturated aqueous NaCl, dried. The solvent was removed under reduced pressure, obtaining an oily residue, which crystallized upon standing. The solid product PE the LASS="ptx2">

1H-PMR (acetone - d6): 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. CaIc. C24H22O4: C 76.99; H, 5.92.

C, 76.74; H, 6.15.

Example 3. (1RS, 2SR, 3SR)-1-(4-Methoxyphenyl)-3- (3,4-methylenedioxyphenyl)indan-2-carboxylic acid.

a) 2-(3,4-Methylenedioxybenzyl)benzoic acid.

To a solution of 2-bromobenzoyl acid (12 g, 0.06 mol) in THF (200 ml) at -100oC in argon atmosphere was added dropwise n-utility (50 ml of 2.5 M solution in hexane, 0.125 mol), keeping the temperature below -90oC. Upon completion of addition the resulting solution was stirred 1 h at -100oC, slowly adding during this time, the solution of acid chloride piperonylic acid (11 g, 0.06 mmol) in THF (50 ml), keeping the temperature below -90oC. the resulting mixture allowed to warm up to -80oC and stirred for 1 hour, then gave to slowly warm to room temperature and left to stand for 48 hours, the Reaction mixture was concentrated under reduced pressure, and the residue was distributed between Et2O and 1 M HCl. The organic phase was extracted with 10% aqueous NaOH. NaOH extract was acidified end) and concentrated under reduced pressure. The residue was purified instant chromatography on silica gel, elwira with a gradient solvent of 10 to 30% EtOAc In (0.1% HOAc) hexane to obtain named in the title compound in the form of not-quite-white solid product (4.5 g, 28%).

(b) Diethyl 2-[2-(3,4-methylenedioxybenzyl)benzylmalonate.

A solution of 2-(3,4-methylenedioxybenzyl)benzoic acid (4.0 g, of 14.8 mmol) in thionyl chloride (30 ml) was heated to boiling under reflux for 2 h, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in Et2O (50 ml) and to this solution was added a solution of diethyl magnesium malonate prepared by the method of Walker and Hauser, JACS, 68, 1386 (1946), using (0.8 g, 33.3 mmol) and diethyl of malonate (4.9 g, 30.6 mmol) in Et2O. the resulting mixture was heated to boiling under reflux for 1 h, then allowed to cool and poured into ice water (H2SO4(100 ml). The aqueous phase was extracted with Et2O, and the combined organic product was washed with saturated aqueous NaCl and dried. The solvent was removed under reduced pressure to obtain named in the title compound in the form of organic oil which was used without far is Amy diethyl 2-[2-(3,4-methylenedioxybenzyl) benzylmalonate (untreated substance, prepared above) in 5% aqueous Na2CO3(100 ml) was heated to boiling under reflux for 10 minutes the Reaction mixture gave then cooled and the aqueous portion was removed by decantation. The residue was placed in H2O (50 ml) and the mixture was heated to boiling, cooled and concentrated under reduced pressure. The residue was recrystallize from hexane to obtain named the title compound as a yellow solid (5.0 g, 100% for two steps).

d) Ethyl (1RS, )-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)inden-2-carboxylate.

A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O /THF (10 ml) was added to the magnesium turnings (0.105 g, 5.0 mmol) and the resulting mixture allowed to mix for 30 minutes, the 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxenden-2-carboxylate (0.77 g, 2.4 mmol) in 10:1 Et2O/THF (55 ml) at 0oC. the resulting mixture was stirred at 0oC 1 h and then was distributed between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified of mcneven altago glassy solid product (0.80 g, 80%).

e) Ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) inden-2-carboxylate.

To a solution of ethyl (1RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) -inden-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2(10 ml) at 0oC in argon atmosphere was added triethylsilane (0.28 g, 2.4 mmole) and subsequently, boron TRIFLUORIDE, everet (1 ml, 8.1 mmole). The resulting solution was stirred at 0oC 10 min, and then was distributed between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure and the residue was filtered through a layer of silica gel, elwira CH2Cl2. Named the title compound (see 1 and 2 of the double bond isomers) was obtained as a glassy yellow solid (0,72 g, 94%).

(f) Ethyl (1RS, 2RS, 3SR)-1-(4-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)inden-2-carboxylate.

To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)- inden-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 in an atmosphere of H256 h and was filtered. The filtrate was concentrated under reduced pressure to obtain named in the title compound in dimethoxyphenyl-3-(3,4-methylenedioxyphenyl) indan-2 carboxylic acid.

To a solution of ethyl (1RS,2RS,3SR)-1-(4-methoxyphenyl)-3- (3,4-methylenedioxyphenyl)indan-2 carboxylate (0.10 g, 0.2 mmol) in EtOH (5 ml) was added a solution of sodium hydroxide (0.10 g, 2.5 mmole) in H2O (2 ml) the resulting mixture was stirred at room temperature overnight. The mixture was acidified and the resulting solid product was collected by filtration and dried under reduced pressure to obtain named the title compound as a tan solid (0.04 g, 86%).

1H NMP (CDCl3): 7.25 (m, 5H); 6,90 (m, 4H); 6,77 (d, 2H, J = 7 HZ); 5,95 (m, 2H); br4.61 (d, 2H, J = 10 HZ); 3,81 (S, 3H); of 3.25 (t, 2H, J = 10 H). MS: 387(M - H+].

Anal. CaIc. C24H20O51/8 H2O : C, 73.79; H, 5.22.

C, AT 76.73; H, 5.21.

Example 4. (1RS, 2SR, 3SR)-1-(4-forefeel)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid.

a) Ethyl (1RS)-1-(4-forefeel)-1-hydroxy-3-(3,4 - methylenedioxyphenyl)inden-2-carboxylate.

To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxenden-2 - carboxylate (100 mg, 0.31 mmol) in THF (5 ml) in an argon atmosphere at 0oC was added a solution of freshly prepared 4-forefeel magnesium bromide (of 0.62 mmol). After stirring for 45 min the mixture was distributed between 3M HCl and EtOAc. The organic extract posledovatelna the residue was purified instant chromatography, elwira 15% EtOAc /hexane to obtain named the title compound (45 mg, 35%).

b) Ethyl (RS)-1-(4-forefeel)-3-(3,4-methylenedioxyphenyl) inden-2-carboxylate

To a solution of ethyl (1RS)-1-(4-forfinal)-1-hydroxy-3-(3,4 - methylenedioxyphenyl)inden-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2(3 ml) at 0oC added triethylsilane (38 μl, 0.24 mmol), and subsequently, boron TRIFLUORIDE, everet (121 μl, 0.98 mmole). The reaction mixture is allowed to warm to room temperature and was stirred for 15 minutes, slowly adding during this time of 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively H2O, 5% aqueous NaHCO3and saturated aqueous NaCl. The solvent was removed under reduced pressure to obtain named the title compound (40 mg, 90%) as a mixture of 1 and 2 isomers of the double bond.

c) Ethyl (1RS, 2RS, 3SR)-1-(4-forefeel)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylate.

To a solution of ethyl (RS)-1-(4-forefeel)-3-(3,4 - methylenedioxyphenyl)inden-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 in an atmosphere of H2during the night, then was filtered through a layer of Celite. The filtrate was concentrated under reduced Yes the TCI.

d) (1RS, 2SR,3SR)-1-(4-forefeel)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid.

To a solution of ethyl (1RS,2RS,3SR)-1-(4-forefeel)-3-(3,4 - methylenedioxyphenyl)indan-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 allowed to mix at room temperature overnight, then concentrated under reduced pressure. The residue is distributed between the H2O and Et2O. the Aqueous phase was acidified with 3M HCl and was extracted with EtOAc several times. The combined EtOAc extracts were washed successively H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure to obtain oil, which was led from EtOAc /hexane. Named in the title compound was obtained as an almost white crystalline solid (22 mg, 39%); so pl. 146 - 149oC.

1H-NMP (CDCl3): 7.23 (m, 4H); of 6.96 (m, 1H); 6.90 (m, 1H), 6,79 (S, 2H); 6.75 (S, 1H); 5.96 (m, 2H); 4.62 (apparent br t, 2H, J = 10 HZ); 3.25 (t, 1H, J = 10 HZ).

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

Anal. CaIcd. C23H17FO4: C, 73.40; H, 4.55.

Found: C, At 73.19; H, 4.45.

Example 5. (1RS, 2SR, 3SR)-1-(3-Methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid.

a) Ethyl (1RS)-1-hydroxy-1-(3-m)-1-oxenden-2 - carboxylate (100 mg, 0.31 mmol) in THF (2 ml) in an argon atmosphere at 0oC was added a solution of freshly prepared 3-methoxyphenyl magnesium bromide (0.31 mmol). After stirring for 15 min additionally added 3-methoxyphenyl magnesium bromide (0.06 mmol). Stirring is continued for 45 minutes by this time analysis by thin-layer chromatography showed that the reaction is complete. Additionally added 3-methoxyphenyl magnesium bromide (0.12 mmol). After stirring for a further 2 h the mixture was distributed between 3M HCl and EtOAc. The organic extract was successively washed H2O, 5% aqueous NaHCO3H2O and saturated aqueous NaCl. The solvent was removed under reduced pressure and the residue was purified instant chromatography, elwira 15% EtOAc /hexane to obtain named the title compound (150 mg, 100%).

b) Ethyl (1RS)-1-(3-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)inden-2-carboxylate.

To a solution of ethyl (1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)-inden-2-carboxylate (150 mg, 0.35 mmole) in CH2Cl2added triethylsilane (67 μl, 0.42 mmol) and subsequently, boron TRIFLUORIDE, everet (213 μl, 1.73 mmol). The reaction mixture allowed to mix for 30 min, slowly adding during this time, 5% aqueous HCl. The mixture ekstragirovannymi NaCl and dried (MgSO4). The solvent was removed in vacuo and the residue was purified instant chromatography, elwira 10% EtOAc /hexane to obtain named the title compound (45 mg, 31%) as a mixture of 1 and 2 isomers of the double bond.

c) Ethyl (1RS, 2RS, 3RS)-1-(3-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylate.

To a solution of ethyl (RS)-1-(3-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)inden-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 at hydrogenator Parra at 50 psi (10.546 kg/cm2) H2during the night, then was filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to obtain named the title compound (43 mg, 94%) which was used without further purification.

d) (1RS, 2SR,3SR)-1-(3-Methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid.

To a solution of ethyl (1RS,2RS,3SR)-1-(3-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylate (43 mg, 0.10 mmole) in EtOH (1 ml) was added 6M KOH (0.10 ml, 0.60 mmol). The resulting mixture allowed to mix at room temperature overnight, then distributed between the H2O and Et2O. the Aqueous phase was acidified with 3M HCl and was extracted several 4). The solvent was removed under reduced pressure to obtain oil, which was led from Et2O /hexane. The named compound is obtained in the form of a solid product with so pl. 131 - 133oC.

1H NMR (CDCl3: 7.21 (m, 3H); 6,97 - 6.73 (m, 8H); 5.95 (m, 2H); br4.61 (apparent br t, 2H, J = 9 HZ); 3.67 (S, 3H); 3.30 (t, 1H, J = 9 HZ).

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

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

Found : C, 74.74; H, 5.47.

Example 6. (1RS,3SR)-1,3-Di-(3,4-methylenedioxyphenyl)- indan-2-carboxylic acid.

a) Ethyl (1RS)-1-di-(3,4-methylenedioxyphenyl)-1-hydroxide-2 - carboxylate.

To dry the magnesium shavings (0.25 g, 10 mmol) in an argon atmosphere was added 4-bromo-1,2-methylenedioxybenzene (2.1, 10 mmole) in 1:10 THF / Et2O (22 ml). The resulting solution was allowed to mix at room temperature for 2 hours During this time additionally added THF (4 ml). Obtained 3,4-methylenedioxyaniline bromide was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxenden-2 - carboxylate (0.50 g, 2 mmole) in 1:4 THF/Et2O (25 ml) in an argon atmosphere at 0oC. the resulting mixture was stirred at 0oC for 15 minutes, during this time, added 1M HCl (50 ml). The phases were separated and the aqueous phase was extracted with Et2O. Oil under reduced pressure and the residue was purified instant chromatography, elwira 10% EtOAc / hexane to obtain named the title compound as a yellow solid product (0,29 g, 42%).

b) Ethyl (RS)-1-1,3-di-(3,4-methylenedioxyphenyl)inden-2 - carboxylate.

To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1 - hydroxide-2-carboxylate (0.29 grams, of 0.65 mmol) in CH2Cl2(3 ml) at 0oC in argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), and subsequently, boron TRIFLUORIDE, everet (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 minutes, during this time, added ice 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, the residue was placed on a small layer of silica gel, elwira CH2Cl2to get named in the title compound (257 mg, 92%).

c) Ethyl (1RS,3RS)-1,3-di-(3,4-methylenedioxyaniline-2 - carboxylate.

The ethyl (RS)-1,3-di-(3,4-methylenedioxyphenyl)inden-2-carboxylate (163 mg, 0.38 mmol) was placed in MeOH (0.05 ml) and to this mixture was added SmI2(10 ml of 0.1 M solution in THF, 1.0 mmol). The resulting mixture was stirred in an argon atmosphere during the night, by which time analysis by thin-layer chromatography showed that the reaction was completed. Donnie 2 hours The reaction mixture is distributed between Et2O and 5% aqueous Na2S2O3. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified instant chromatography, elwira 10% EtOAc /hexane to obtain named in the title compounds as a colorless, glassy solid (120 mg, 75%).

d) (1RS,3RS)-1,3-di-(3,4-Methylenedioxyphenyl)indan-2-carboxylic acid.

To a solution of ethyl (1RS,3RS)-1,3-di-(3,4-methylenedioxyphenyl)indan - 2-carboxylate (75 mg, 0.17 mmol) in EtOH (20 ml) was added NaOH (0.10 g, 2.5 mmol). The resulting mixture allowed to mix at room temperature for 3 days, by which time thin layer chromatography showed that the reaction was completed. The mixture was then heated to boiling under reflux for 36 h, allowed to cool and concentrated under reduced pressure. To the residue was added concentrated HCl and the resulting solid product was collected by filtration and dried. The solid product was ground into powder with boiling hexane to obtain named the title compound as a white solid (50 mg, 73%); so pl. 182 - 185oC.

1HNMP (CDCl3), 7.25 (m, 2H); 7.15 (m>); 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)+< / BR>
Anal : CaIcd. C24H18O61/5 H2O: C, 71.00; H, 4.52.

Found : C, 71.13; H, 4.46.

Example 7. (TRANS,TRANS)-1,3-di-(3,4-Methylenedioxyphenyl)indan - 2-carboxylic acid.

a) Ethyl (CIS,CIS)-1,3-di-(3,4-methylenedioxyphenyl)-indan-2 - carboxylate.

To a solution of ethyl (RS)-1,3-di-(3,4-methylenedioxyphenyl)inden-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 at hydrogenator Parra at 55 psi (10.898 kg/cm2in the atmosphere of H2within 2 days, then was filtered through a layer of celite. The filtrate was concentrated under reduced pressure to obtain the titled compound (45 mg, 48%) as a glassy yellow solid, which was used without further purification.

b) (TRANS,TRANS)-1,3-di-(3,4-Methylenedioxyphenyl)-indan-2 - carboxylic acid.

To a solution of ethyl (CIS,CIS)-1,3-di-(3,4-methylenedioxyphenyl)indan-2-carboxylate (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 mix at room temperature in techny solid product was collected by filtration and dried. The solid product was recrystallize from Et2O / hexane to obtain named in the title compound in the form of a solid light-reddish-brown (12 mg, 30%); so pl. 188 - 191oC.

Example 8. (1RS, 2RS, 3SR)-1-(3,4-Methylenedioxyphenyl)-3 - phenylindane-2-carboxylic acid.

a) Ethyl (1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3 - phenylindane-2-carboxylate.

To a solution of ethyl 1-oxo-3-phenylindane-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) in an argon atmosphere at 0oC was added to a solution of freshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min the mixture was distributed between 3M HCl and EtOAc. The organic extract was washed successively H2O, 5% aqueous saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified instant chromatography, elwira 10% EtOAc/hexane to obtain named in the title compounds (1,03 g, 72%).

b) Ethyl (RS)-1-(3,4-methylenedioxyphenyl)-3-phenyl-inden-2 - carboxylate.

To a solution of ethyl (1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3 - phenylindane-2-carboxylate (1,03 g of 2.58 mmole) in CH2Cl1(40 ml) was added triethylsilane (0,49 ml of 3.07 mmol) and subsequently Bor t is bavili 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively H2O, 5% aqueous NaHCO3and saturated aqueous NaCl. The solvent was removed under reduced pressure to obtain named in the title compounds (1,00 g, 100%) as a mixture of 1 and 2 isomers of the double bond.

c) Ethyl (1RS,2SR,3SR)-1-(3,4-methylenedioxyphenyl)-3-phenylindane - 2-carboxylate.

To a solution of ethyl (RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindane-2 - carboxylate (1.00 g, 2.60 mmol) in (25 ml) was added 10% palladium on activated carbon (30 mg). The resulting suspension was stirred in an atmosphere of H2throughout the night. When the analysis thin-layer chromatography showed that the reaction had ended, added an additional 10% palladium on activated carbon (30 mg) and the mixture was shaken in hydrogenator Parra at 30 psi (2.109 third-party product kg/cm2) H2within 2 days. By this time analysis by thin-layer chromatography again showed that the reaction is complete. The reaction mixture was filtered through a layer of Celite and added 10% palladium on activated carbon (250 mg). The reaction mixture was shaken at hydrogenator Parra at 60 psi (4.218 kg/cm2) H2throughout the night. Filtering and repeat the last conditions of hydrogenation led to the complete expenses and under reduced pressure to obtain named the title compound (650 mg, 65%, which was used without further purification.

d) (1RS, 2RS,3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2 - carboxylic acid.

To a solution of ethyl (1RS, 2SR,3SR)-1-(3,4-methylenedioxyphenyl)-3 - phenylindane-2-carboxylate (650 mg, 1.68 mmol) in EtOH containing a few drops of THF, was added 6M KOH (1.68 ml, 10.1 mmol). The resulting mixture allowed to mix at room temperature overnight, then concentrated under reduced pressure. The residue is distributed between the H2O and Et2O. the Aqueous phase was acidified with 3M HCl and was extracted with EtOAc several times. The combined EtOAc extracts were washed successively H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure to obtain oil, which crystallized from EtOAc/hexane. The named compound are obtained in the form of a solid (305 mg, 51%); so pl. 186 - 187oC.

Anal. CaIcd. C23H18O4: C, 77.08; H, 5.06.

Found : C, At 76.60; H, 5.08.

Example 9. (1RS, 2SR, 3SR)-1-(4-Methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)-2-(tetrazol-5-yl)-indan.

a) (1RS, 2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxamide.

A mixture of (1RS, 2SR, 3SR)-1-(4-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic sour is concentrated under reduced pressure, and the residue was dissolved in benzene (5 ml). To the mixture was added in an argon atmosphere concentrated NH4OH (5 ml). The formed solid product was collected by filtration, washed H2O and dried under reduced pressure to obtain named the title compound (185 mg, 75%).

b) (1RS, 2SR,3SR)-1-(4-Methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carbonitrile.

To ice DMF (1 ml) in an argon atmosphere was added oxalyl chloride (68 μl, 0.78 mmol). After stirred for 5 min at 0oC, was added a solution of (1RS,2SR,3SR)-1-(4-methoxyphenyl)- 3-(3,4-methylenedioxyphenyl)indan-2-carboxamide carboxamide (150 mg, 0.39 mmol) in DMF (2 ml), and additionally continued stirring 10 minutes at 0oC. the Reaction mixture was distributed between EtOAC and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively H2O, aqueous NaHCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure to obtain named the title compound as a white solid (135 mg, 94%) which was used without further purification.

c) (1RS, 2SR, 3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl) -2-(tetrazol-5-yl)indan.

oC for 5 min, then cooled to room temperature. To the reaction mixture was added a solution of (1RS,2SR,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) -indan-2-carbonitrile (125 mg, 0.34 mmol) in THF (2.5 ml). After heating at 70oC during the night the analysis of the reaction mixture by thin-layer chromatography showed the presence of starting material, therefore, was prepared additional amount AI(N3)3as described above (of 1.34 mmol) in THF. To this mixture was added to the reaction mixture and heated at 70oC, continued an additional 5 hours, the Mixture was distributed between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure, and the residue was led from EtOAc/hexane to obtain named the title compound (78 mg, 56%). Part of this product was further purified by the method of MPL C (repeated preparative thin-layer chromatography (Lichroprep RP-18, MeOH/H2O = 60/40) and then by recrystallization; so pl. 155 - 157oC (EtOAc /hexane).

1H NMR (CDCl3): 7.28 - 7.15 (m, 4H); 7.03 - 6.95 (m, 2H); 6.87 - 6.84 (m, 2H); 6.74 (S, 3H); 5.94 (d, 1H,MS (m/e) : 413.2(M + H)+].

Example 10. (1RS, 2SR, 3RS)-1-(2-Methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid.

a) Ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)inden-2-carboxylate.

To dry the magnesium shavings (81 mg, 3.4 mmol) in an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2O (3 ml). Part of the resulting solution of 2-methoxyphenyl magnesium bromide (0.45 ml, 0.51 mmole) was added dropwise to a solution of ethyl 3-(3.4-methylenedioxyphenyl)-1-oxenden-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) in an argon atmosphere at 0oC. After stirring for 15 min the mixture was distributed between 3M HCl and EtOAc. The organic extract was washed successively H2O, 5% aqueous NaHCO3H2O and saturated aqueous NaCl. The solvent was removed under reduced pressure and the residue was purified instant chromatography, elwira 15% EtOAc/hexane to obtain named the title compound (100 mg, 68%).

b) Ethyl (RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) inden-2-carboxylate.

To a solution of ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)inden-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2(5 ml) was added triethylsilane (32 mg, 0.28 mmol), and later Bo is 10 min, during this time slowly added 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively H2O, 5% aqueous NaHCO3H2O and saturated aqueous NaCl and dried (MgSO4. The solvent was removed under reduced pressure to obtain named the title compound (91 mg, 96%) as a mixture of 1 and 2 isomers of the double bond.

c) Ethyl (1RS, 2RS, 3RS)-1-(2-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylate.

To a solution of ethyl (RS)-1-(2-methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)inden-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 at hydrogenator Parra at 60 psi H2during the night, then was filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to obtain named the title compound (90 mg, 100%) which was used without further purification.

d) (1RS, 2SR,3RS)-1-(2-Methoxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid.

To a solution of ethyl (1RS,2RS,3RS)-1-(2-methoxyphenyl)-3- (3,4-methylenedioxyphenyl)indan-2-carboxylate (90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF, was added 6M KOH (0.22 ml, of 1.32 mmol). The resulting mixture allowed to stir is Lili between the H2O and Et2O. the Aqueous phase was acidified with 3M HCl and was extracted with EtOAc. The EtOAc extract was washed successively H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure to obtain named the title compound (40 mg, 49%).

1H NMP (CDCl3): 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 (S, 3H); 3.38 (t, 1H, J=10 HZ).

Example 11. (1RS, 2SR, 3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl) indan-2-carboxylic acid, sodium salt

a) 3-Benzyloxyacetophenone.

To a mixture of sodium hydride (4.5 g, 80% dispersion in mineral oil, 0.15 mol), which was exempt from mineral oil by washing in DMF (25 ml) was added dropwise while cooling a solution of 3-hydroxyacetophenone (20.5 g, 0.15 mol) in DMF (25 ml). After complete addition, the mixture allowed to mix at room temperature for 15 minutes, during this time, added benzyl bromide (25.6 g, 0.15 mol). The resulting mixture allowed to mix at room temperature overnight, then was distributed between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed sequentially 1M NaOH, H2O and saturated aqueous NaCl and dried. The solvent ugly without further purification.

b) Methyl 2-(3-benzyloxy)benzoylacetate.

To a mixture of sodium hydride (28.3 g of 80% dispersion in mineral oil, 0.94 mol), which was exempt from mineral oil by washing, dimethyl carbonate (100 ml) in 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 to boiling under reflux for 30 min, then cooled in an ice bath and stopped the reaction by slow addition of 3M HCl, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed successively H2O, aqueous NaHCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure to obtain named in the title compounds (112,5 g, 97%)

c) Methyl 2-(3-benzyloxybenzyl)-3- (3,4-methylenedioxyphenyl)propionate.

A mixture containing methyl 2-(3-benzyloxy)benzoylacetate (75.0 g, 0.26 mol) piperonal (43.6 g, 0.29 mol), acetic acid (3.6 ml) and piperidine (1.2 ml) in benzene (70 ml) was heated to boiling under reflux with azeotropic removal of water. After heating to boiling under reflux for 4 h, the reaction mixture was concentrated under reduced pressure, the C.

d) Methyl (1RS, 2SR)-5-benzyloxy-1-(3,4-methylenedioxyphenyl)- 3-oksidan-2-carboxylate.

To triperoxonane acid (150 ml) at 0oC in argon atmosphere was added methyl 2-(3-benzyloxybenzyl)-3-(3,4 - methylenedioxyphenyl)propanoate (80.0 g, 0.19 mol). Mixture allowed to warm to room temperature and stirred 30 min, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed sequentially NaHCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure and the oily residue was led from EtOAc/hexane to obtain named the title compound (51.3 g, 64%); so pl. 148 - 150oC.

e) Methyl 5-benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxenden-2 - carboxylate.

To a solution of methyl 5-benzyloxy-1-(3,4-methylenedioxyphenyl)-3 - oxonian-2-carboxylate (27.3 g, 65.6 mmol) in benzene (90 ml), cooled in a bath of ice-water was added 2,3-sodium dichloro 5,6-dicyano-1,4-benzoquinone (15,4 g, 67.8 mmol). The resulting mixture was stirred at 0oC 1 h, allowed to warm to room temperature over 1.5 h, and finally was heated to 40oC for 1 hour. The formed solid product was removed by filtration and washed with benzene. The combined filtrate and wash in Sydenham aqueous NaCl and dried. The solvent was removed under reduced pressure, and the residue was led from EtOAc /hexane to obtain named the title compound (16.4 g, 60%) as a red crystalline solid connections; so pl. 140 - 141oC.

f) Methyl (3RS)-5-benzyloxy-3-hydroxy-3-(4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)inden-2-carboxylate.

To dry magnesium turnings (0.96 g, 40 mmol) in an argon atmosphere was added a solution of 4-bromoanisole (7.48 g, 40 mmol) in 9:1 Et2O /THF (50 ml). The resulting solution of 4-methoxyphenyl magnesium bromide was added in portions to a solution of methyl 5-benzyloxy-1-(3,4 - methylenedioxyphenyl)-3-oxenden-2-carboxylate (8,29 g, 20 mmol) in THF (250 ml) in an argon atmosphere. Upon completion of the addition, the mixture is abruptly cooled by adding 3M chilled HCl and was extracted with EtOAc. The organic extract was washed successively H2O, aqueous NaHCO3H2O and saturated aqueous NaCl. The solvent was removed under reduced pressure to obtain named in the title compounds (11.58 g, 100%) which was used without further purification.

(g) Methyl (RS)-5-benzyloxy-3-(4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)inden-2-carboxylate.

To a solution of methyl (3RS)-5-benzyloxy-3-hydroxy-3- (4-methoxyphenyl)-1-(3,4-m the ore argon, at 0oC added triethylsilane (3.9 ml, 23.6 mmol) and subsequently, boron TRIFLUORIDE, everet (14.7 ml, 120 mmol). The reaction mixture was stirred 10 min at 0oC the mixture was distributed between 3M HCl and EtOAc. The organic extract was washed successively H2O, aqueous NaHCO3H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure, and the residue was purified instant chromatography, elwira with a gradient solvent of 25 - 45% Et2O /hexane. Named the title compound (to 8.41 g, 83% for two steps) was isolated as a mixture of 1 and 2 isomers of the double bond.

h) Methyl (1RS,2RS,3SR)-5-hydroxy-3-(4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)indan-2-carboxylate.

To a degassed solution of methyl (RS)-5-benzyloxy-3- (4-methoxyphenyl)-2-(3,4-methylenedioxyphenyl)inden-2-carboxylate (6.60 g, 13,0 mmol) in EtOAc (25 ml) and EtOH (175 ml) was added 5% palladium on activated carbon (0.6 g). The resulting suspension was shaken at hydrogenator Parra at 60 psi H2within 20 hours by this time NMR analysis of the reaction mixture showed that the reaction was completed. The catalyst was removed by filtration through a layer of Celite, and added fresh 5% palladium on activated carbon (0.6 g). The mixture was shaken for gidrometeotsentra under reduced pressure. The residue was led from EtOAc /hexane with the purpose named in the title compound (4.83 g, 89%); so pl. 187 - 188oC.

i) (1RS, 2SR, 3SR)-5-Hydroxy-3-(4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid sodium salt.

To a solution of methyl (1RS,2RS,3SR)-5-hydroxy-3-(4-methoxyphenyl) -1-(3,4-methylenedioxyphenyl)indan-2-carboxylate (150 mg, 0.36 mmol) in EtOH (4 ml) was added 10% NaOH (4 ml) and the resulting mixture allowed to mix in the atmosphere of argon overnight. Added water (5 ml) and the mixture was concentrated 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 H2O and saturated aqueous NaCl and dried. The solvent was removed under reduced pressure. Prepared sodium salt, and a portion of it (100 mg) was purified by reversed-phase chromatography with the aim of obtaining mentioned in the title compound (73 mg, 48%). Rubbing this product from EtOAc gave a white crystalline solid product; so pl. 198oC (decomp.).

1H NMR (MeOH-d4): / 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}+

a) 3-(Prop-1-yloxy)acetophenone.

To a suspension of NaH (13.84 g, 0.58 mol) in dry DMF (50 ml) at 0oC C, was added a solution of 3-hydroxyacetophenone (50 g, and 0.37 mol). After stirring for 30 min was added 1-iodopropane (70 ml, 0.72 mol) and the mixture was stirred over night at room temperature. The mixture was diluted with dry DMF (50 ml) and then added (2.77 g, 0.12 mol) and subsequently 1-iodopropane (23 ml, 0.24 mol). After 1 h TCX showed that the reaction was completed and the product carefully extinguished 6M HCl and was extracted with EtOAc. The EtOAc extract was washed successively: H2O, 10% aqueous NaOH and then with a solution of salt. After drying (MgSO4filtration and evaporation gave named the title compound (65 g, 98%) as a yellow oil which was used without further purification.

b) Methyl 3-(prop-1-yloxy)benzoylacetate.

To a suspension of NaH (12 g, 0.5 mol) in dry dimethyl carbonate (50 ml) was added slowly a solution of 3-(prop-1-yloxy) acetophenone (65 g, and 0.37 mol) in dry dimethyl carbonate (100 ml). While adding esotericist reaction resulted in temperatures up to boiling. After the addition the mixture was mechanically mixed during the night and then carefully extinguished 3M HCl and was extracted with EtOAc. The EtOAc extract was washed sequence is Ivana gave a yellow oil (82 g, quantitative) which was used without further purification.

c) Methyl(1RS, 2SR)-1-(3,4-Methylenedioxyphenyl)-5- (prop-1-yloxy)-3-oxo-indan-2-carboxylate.

To a solution of methyl-3-(prop-1-yloxy)benzoylacetate (10 g, 4.2 mmol) in benzene (50 ml) was added 3,4-methylene dioxybenzene (6.36 g, 4.2 mmol) and then piperidine (0.42 ml, 0.42 mmol) and glacial acetic acid (approx. 8 drops). The mixture was heated to boiling under reflux for 2 h and the volatile products were removed under reduced pressure, obtaining methyl (Z)-3-(3,4 - methylenedioxyphenyl)-2-3-(prop-1-yloxy)-benzoyl propionate in the form of a yellow oil. This residue was dissolved in triperoxonane acid (50 ml) and the mixture was stirred at room temperature for 20 minutes Triperoxonane acid was removed under reduced pressure to obtain named the title compound as a dark oily residue (16 g) which was used in the next stage without purification.

1H NMR (CDCl3) inter alia 7.85 (1H, S); 7.56 - 7.30 (3H, m); 7.08 - 7.15 (1H, m); 6.95 (1H, dd, J=8, 2 HZ); 6.78.

d) Methyl-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)-1-oxo - inden-2-carboxylate.

Methyl (1RS, 2SR)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-3 - oxo-indan-2-carboxylate (16 g, crude product and the under reflux for 2 h, then cooled, filtered and the solvent removed under reduced pressure. The product was purified instant column chromatography on silica gel (eluent: EtOAc/hexane, 20:80) to obtain named the title compound as an orange solid (5.2 g, 31% over two stages); so pl. 125 - 126oC.

e) Methyl(1RS)-1-(2-benzyloxy-4-methoxyphenyl)-1-hydroxy-3-(3,4 - methylenedioxyphenyl)-6-(prop-1-yloxy)inden-2-carboxylate.

To dry magnesium turnings (0.15 g, 6.25 mg, atoms) in the atmosphere of argon was added in portions a solution of 2-benzyloxy-4-methoxyphenol (preparation see below) (1.80 g, 6.15 mmol) in 5% THF/diethyl ether (7 ml). The obtained 2-benzyloxy-4-methoxyphenyl magnesium bromide was added to a solution of methyl-3-(3,4-methylenedioxyphenyl)-6-(prop-1 - yloxy)-1-oxo-inden-2-carboxylate (1.5 g, 4.1 mmol) in Et2O (65 ml) in an argon atmosphere at 0oC. the resulting solution was allowed to warm to room temperature and was stirred 10 minutes, the Mixture was distributed between 3M HCl (30 ml) and EtOAc (75 ml). The organic extract was washed successively H2O, aqueous NaHCO3H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed under reduced pressure, the residue was purified instant chromatographie the oil (1.4 g, 59%).

f) Methyl-(RS)-3-(2-benzyloxy-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)inden-2-carboxylate.

To a solution of (1.35 g, 2.33 mmol) in CH2Cl2(20 ml) at 0oC in argon atmosphere was added triethylsilane (0.47 ml, 2.94 mmol), and subsequently, boron TRIFLUORIDE, everet (1.4 ml, 11.4 mmol). The resulting solution was stirred at 0oC 10 min then distributed between 1M HCl and the organic extract was washed successively H2O, 5% aqueous NaHCO3H2O and salt solution. After drying (Na2SO4) the solvent was removed under reduced pressure and the product was purified column chromatography on silica gel (eluent: EtOAc/hexane, 25:75). Named the title compound (as a separate indefinite double bond isomer) was obtained as a yellow oil (0.65 g, 50%).

(g) Methyl(1RS,2RS,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylate.

Methyl-(RS)-3-(2-benzyloxy-4-methoxyphenyl)-1-(3,4 - methoxy-phenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)- inden-2-carboxylate (0.64 g, 1.13 mmol) was dissolved in a small volume of EtOAc and added EtOH (25 ml) and then 10% palladium on activated carbon (0.2 g). The resulting solution was stirred Atmos column chromatography on silica gel (eluent: EtOAc/hexane, 30:70) to obtain named the title compound as colourless solid (0.21 g, 39%); so pl. 155 - 156oC.

h) Methyl(1RS, 2RS, 3RS)-3-(2-carbomethoxy-4-methoxyphenyl) -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylate.

A solution of methyl(1RS, 2RS, 3RS)-3-(2-hydroxy-4-methoxyphenyl) -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylate (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 added ethyl bromoacetate (0.016 ml, 0.14 mmol). After 20 min the reaction was stopped by mixing products with 3M HCl and cooled mixture was extracted with EtOAc, the EtOAc extract was washed with water and then with a solution of salt, dried (MgSO4), was filtered and was evaporated. Product purification column chromatography on silica gel (eluent: EtOAc/hexane, 30:70) to obtain named in the title compounds as a pale yellow oil (0,05, 85%).

i) (1RS, 2SR,3RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

To a solution of methyl(1RS, 2RS, 3RS)-3-(2-carbomethoxy-4 - methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2 - carboxylate (0.05 g, 0.089 mmol) in EtOH (which was divided between EtOAc and 3M HCl. The organic extract was washed H2O and then a solution of salt, dried (MgSO4), was filtered and was evaporated to obtain a colorless oil. The product was led from Et2O/hexane to obtain named in the title compound in the form of not-quite-white solid (0.03 g, 65%); so pl. 195 - 198oC.

1H NMR [(CD3)2CO] 7.17 (1H, d, J=9.1 HZ); 6.8 - 6.71 (5H, m); 6.55 - 6.47 (3H, m); 5.94 (2H, S); 4.97 (1H, br, d); 4.73 (1H, d, J=16.5 HZ); 4.63 (1H, d, J=16.5 HZ) 4.52 (1H, d, J=7 HZ); 3.80 - 3.76 (2H, m); 3.76 (3H, S); of 3.48 - 3.35 (1H, br, m); 1.65 (2H, sextet = 7.4 HZ); 0.92 (3H, t, J=7.4 HZ). MS: 538(M+NH4)+].

Anal. CaIc. C29H28O9: C, 66.92; H, 5.42.

C, 67.37; H, 5.32.

Example 12a.

Preparation of 2-benzyloxy-1-bromo-4-methoxybenzene.

a) 1-Bromo-2-hydroxy-4-methoxybenzo.

3-Bromo-2-hydroxy-6-methoxybenzoic acid.

[J. de Paulis et al., J. Med. Chem. (1985), 28, 1263-1269] (5 g, 0.02 mol) was heated in quinoline (200 ml) at 160oC for 1 h While cooling, the product was distributed between Et2O and 3M HCl. The organic extract was washed with water and salt solution and dried (MgSO4), was filtered and was evaporated to obtain named the title compound as a light brown oil (4 g, 97%). This 1.5 HZ); 6.43 (1H, dd, J=9.1 5HZ).

b) 2-Benzyloxy-1-bromo-4-methoxybenzoyl.

To a suspension of NaH (1.01 g, 0,042 mol) in dry DMF (ml) at 0oC was added a solution of 1-bromo-2-hydroxy-4-methoxybenzene (7 g, 0.035 mol). After stirring at room temperature for 30 min the solution was cooled to 0oC and added benzyl bromide (6.24 ml, 0.052 mmol). The mixture was heated to room temperature for 20 min and then gently stopped the reaction by adding 3M chilled HCl and was extracted with EtOAc. The EtOAc extract was washed successively H2O, 5% aqueous NaHCO3H2O and finally with a solution of salt. After drying (MgSO4filtration and evaporation gave a dark colored oil. The product was purified instantaneous columnar chromatography (eluent: EtOAc/hexane, 20:80) to obtain named the title compound as a colourless oil (7.5 g, 73%).

1H NMR (CDCl3) 7.50 - 7.25 (6H, m); 6.51 (1H, d, J=1.5 HZ); to 6.39 (1H, d, J=9HZ); 5.09 (2H, S); 3.72 (3H, S).

Example 13. (1RS,2SR,3RS)-3-[2-(3-Hydroxyprop-1 yloxy)-4 - methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 - carboxylic acid, salt of dicyclohexylamine.

Methyl (1RS, 2RS,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-ka is massively at ambient temperature for 20 min, then added 3-bromopropane-1-ol (37 μl, 0.41 mmol). After stirring for 1 h the product was distributed between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water and then the salt solution, then dried (MgSO4betwedn. ), was filtered and was evaporated to obtain oil. The product was purified column chromatography to obtain methyl (1RS,2SR,3RS)-3-[2-(3-hydroxyprop-1 yloxy)-4-methoxyphenyl-1- (3,4-methylenedioxyphenyl]-5-(prop-1-yloxy)indan-2-carboxylate (0.1 g, 65%) (WDI has shown that there has been some epimerization at C-2). This product was used without further purification. Methyl (1RS, 2SR, 3RS)-3-[2-(3-hydroxyprop-1 yloxy) -4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan - 2-carboxylate (0.04 g, 0.075 mmol) was dissolved in methanol (2 ml) and added aqueous potassium hydroxide (2M, 0.22 ml, 0.44 mmol). The mixture was stirred while heating to boiling point with a reverse refrigerator overnight, then cooled, diluted with water, acidified with 3M aqueous hydrochloric acid and was extracted with ethyl acetate. The organic extract was washed with water and a solution of salt, dried (MgSO4anhydrous), filtered and evaporated to obtain oil. The product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane/ 3% of uksosn - 112oC.

Example 14. (1RS,2SR,3RS)-3-[2-(1-Carboxylat-2-yloxy)-4 - methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)- indan-2-carboxylic acid, salt of bis-dicyclohexylamine.

(1RS, 2SR, 3RS)-3-2-(3-Hydroxyprop-1 yloxy)-4-methoxyphenyl-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid (0.07 g, 0.13 mmol) was dissolved in dry dichloromethane (0.5 ml) and added periodinane Dess-Martin a (0.07 g, 0.17 mmol) in dry dichloromethane (1 ml). After 2 h, the product was distributed between diethyl ether and saturated aqueous sodium carbonate containing sodium thiosulfate. The ether extract was washed with water, then with a solution of salt, dried (MgSO4anhydrous), filtered and evaporated to obtain an oil, which was used without purification. The crude product was dissolved in t-butanol (5 ml) and to this solution was added a solution of sodium chloride (18 mg, 0.2 mmol) and sulfamic acid (21 mg, 0.22 mmol) in water (1.5 ml). After stirring for 1 h at ambient temperature the product was extracted with ethyl acetate. The organic layer was washed with water, then the salt solution and then dried (MgSO4betwedn.), was filtered and evaporated to obtain oil. Product purification column chromatography on silica gel (eluent: etiologically. So pl. 160 - 162oC.

MS (exach mass) M+: 534.1879 (freedi-acid) ( = +1.1 mDA for C30H30O9)

According to the above procedures the following compounds in examples 15 to 29.

Example 15. (1RS)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylic acid. So pl. 191 - 193oC.

m.p. 191 - 193oC

Anal. C23H18O3. (C, 80.68; H, 5.30

C, 80,54; H, 5.33

Example 16. (TRANS,TRANS)-1,3-Diphenylethan-2-carboxylic acid. So pl. 164 - 165oC.

m.p. 164 - 165oC

MS (m/e) : 332 [(M + NH4)+].

Example 17. (1RS,2RS,3SR)-1-(4-Hydroxyphenyl)-3-phenylindane-2 - carboxylic acid.

MS (m/e) : 331 [(M + H)+].

Example 18. (1RS,2RS,3SR)-1-(4-Carboxyphenyl)-3-phenylindane-2 - carboxylic acid.

MS (m/e) : 359(M + H)+].

Example 19. (1RS,2RS,3SR)-1-(3-Methoxyphenyl)-3-phenylindane-2 - carboxylic acid.

MS (m/e) : 362(M + NH4)+].

Example 20. (1RS, 2RS, 3SR)-1-(4-Ethylphenyl)-3-phenylindane-2 - carboxylic acid.

So pl. 163 - 164oC.

MS (m/e) : 360(M + NH4)+]

Anal. CaIcd. C24H22O2: C, 84.18; H 6.48 IN.

Found C, 84.24; H, 6.73.

Example 21. (1RS,3RS)-1,3-Diphenylethan-2-carboxylic acid.

So pl. 210 - 211oC.

): 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 H).

Example 23. (1RS,2RS,3SR)-1-(4-Acetamidophenyl)-3-(4-methoxyphenyl) -indan-2-carboxylic acid.

So pl. 231 - 232oC.

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

Anal. Calcd. C25H23NO4, 1/2 H2O: C, 73.12; H, 5.85; N, 3.41. Found: C, 72.92; H, 5.61; N, 3.24.

Example 24. (1RS,2RS,3SR)-1-(4-AMINOPHENYL)-3-(4-methoxyphenyl)- indan-2-carboxylic acid, salt of dicyclohexylamine

So pl. 187 - 190oC.

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

Example 25. (1RS, 2SR,3SR)-1-(4-Hydroxyphenyl)-3-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid.

So pl. 94 - 96oC.

MS (m/e): 392.4 [(M + NH4)+].

Example 26. (1RS, 2RS,3SR)-1-(3,4-Acid)-3-(4 - methoxyphenyl)-indan-2-carboxylic acid.

So pl. 126 - 128oC.

MS (m/e rel.int): 807 [(2M + I)+, 35]; 403 [(M - H)-, 100].

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

Example 27. (1RS, 2RS,3SR)-1-(3,4-Methylenedioxyphenyl)-3-(4 - methylthiophenyl)indan-2-carboxylic acid

MS (exact mass): (M.)+= 404.1074 ( = + 0.8 mDA for C24H20O4S).

Example 28. (1RS,2RS,3SR)-5-SS="ptx2">

MS (m/e): 441.2(M + Na)+].

Example 29. (1RS, 2SR,3SR)-1,3-Bis)of 3,4-methylenedioxyphenyl)-5 - hydroxyine-2-carboxylic acid.

MS (m/e): 436.2 [M + NH4)+].

Example 30. (1RS, 2SR,3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl) -1-(2-methoxy-4,5-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 - carboxylic acid.

Methyl (1RS,2RS,3SR)-5-hydroxy-3-(2-methoxyethoxy-4 - methoxyphenyl)-1-(2-methoxy-4,5-methylenedioxyphenyl)-indan-2 - carboxylic acid was prepared from 23% overall yield from methyl 2-(3-benzyloxy)benzoylacetate according to the method of example 11. 5-Hydroxyl component turned into propilot according to the methodology described in example 12, and this raw material was processed according to the method of example 70 to remove methoxymethyl group with 55% yield. Named in the title compound then according to the methodology described in example 12, with a 42% yield. So pl. 188 - 190oC.

Anal. CaIcd C30H30O10: C, 65.45; H, 5.49.

Found: C, 65.38; H, 5.49.

Example 31. (1RS,2SR,3RS)-3-(2-Methoxyethoxy)-4-methoxyphenyl) -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

So pl. 161 - 163oC.

Example 32. (1RS, 2SR, 3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-to the,2SR,3SR)-3-(2-Carboxymethoxy-4-methoxyphenyl) -1-[(2-prop-1-yloxy)-4,5-methylenedioxyphenyl] -5-(prop-1-yloxy) indan-2-carboxylic acid.

Anal. CaIc. C32H34O100.5 H2O: C, 65.41; H, 6.00.

Found : C, 65.27; H, 5.99

m.p. 196 - 197oC.

Example 34. (1RS,2SR,3RS)-1-(2-Carboxymethoxy-4,5 - methylenedioxyphenyl) -3-(4-methoxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

MS (DCl NH3) m/e : 538.2 (M + NH3)+, 520.2 (M+H)+(exact mass) M+: 520.1733 ( = 0.0 mDA for C29H28O9)

Example 35. (1RS, 2SR, 3RS)-1-(3,4-Methylenedioxyphenyl)-3-[(2 - prop-1-yloxy)phenyl]-5-(prop-1-yloxy)indan-2-carboxylic acid

So pl. 179 - 180oC.

MS (DCl CH4) m/e : 503.2 (M + C2H5)+, 474.1 (M + H)+(exact mass) M+: 474.2034 ( = +0.8 mDA for C29H30O6).

Example 36. (1RS, 2SR,3SR)-3-(2-Hydroxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

So pl. 97 - 98oC.

MS (exact mass) M+: 432.1568 ( = +0.5 mDA for C26H24O6)

Example 37. (1RS,2SR,3RS)-3-(2-Carboxymethoxy)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid

So pl. 169 - 170oC.

Anal. CaIc. C28H26O80,25 H2O: C, AT 67.94; H, 5.40.

Found : C, At 67.75; H, 5.37.

Example 38. (1RS,2SR,3RS)-3-(2-Benzyloxy-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-Carbo)-3-[2-(2-Hydroxic-1 yloxy)-4 - methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid, salt dicyclohexylamine

So pl. 182 - 184oC.

Anal. CaIc. C41H53NO8: C, 71.59; H, 7.77; N, 2.04 Found : C, 71.67; H, 7.66; N, 2.42

Example 40. (1RS, 2SR,3RS)-3-(2-Ethoxy-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

Anal. CaIc. C29H30O7: C, 71.01; H, 6,16;

Found : C, 70.71; H, 6.01

Example 41. (1RS,2SR,3RS)-3-[4-Methoxy-2-(prop-1-yloxy)-1-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

Anal. CaIc. C30H32O7: C, 71.41; H, 6.39;

Found: C, 71.43; H, 6.31.

Example 42. (1RS,2SR,3RS)-3-[4-Methoxy-2-prop-2-yloxy)phenyl] -1-(3,4-Methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

So pl. 75 - 79oC.

Example 43. (1RS,2SR,3RS)-3-[4-Methoxy-2-(-2-methylprop-1 yloxy) -phenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2 - carboxylic acid. So pl. 85 - 89oC.

Example 44. (1RS,2SR,3RS)-3-[4-Methoxy-2-(3-methylbut-1 yloxy) -phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 - carboxylic acid, salt of dicyclohexylamine.

So pl. 150 - 155oC.

Example 45. (1RS,2SR,3RS)-3-[4-Methoxy-2-(3-pyridyloxy)- phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 - carboxylic acid.

Anal. CaIc. C33H31NO7the yl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 carboxylic acid.

Anal. CaIc. C33H31NO70.5 H2O: C, 71.02; H, 5.78; N, 2.51; Found: C, 70.89; H, 5.59; H, 2.37.

Example 47. (1RS,2SR,3RS)-3-[4-Methoxy-2-(2-pyridyloxy)- phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 - carboxylic acid

So pl. 153 - 155oC.

Example 48. (1RS,2SR,3RS)-3-[2-(Hept-1-yloxy)-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid

So pl. 70 - 73oC.

Example 49. (1RS,2SR,3RS)-3-[4-Methoxy-2-(5-tetraisopalmitate)- phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 - carboxylic acid.

So pl. 102 - 105oC.

Example 50. (1RS,2SR,3RS)-3-(2-Cyanoethoxy-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

So pl. 199 - 201oC.

Example 51. (1RS,2SR,3RS)-3-(2-Carboxymethoxy-4 - methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan - 2-carboxylic acid.

Anal. CaIc. C29H29NO8O 5 C4H8O: C, 67.02; H, 5.99; N, 2.52; Found : C, 67.76; H, 5.96; H, 2.56.

Example 52. (1RS, 2SR, 3RS)-5-Acetamido-1,3 - bis(3,4-methylenedioxyphenyl)indan-2-carboxylic acid.

MS m/e 460(M+H}+].

Example 53. (1RS, 2SR,3SR)-5-Amino-1,3-bis(3,4 - methylenedioxyphenyl)-indan-2-carboxylate, a salt of dicyclohexylamine.

a) Ethyl 3-[tri-1-yl/stannyl]benzoate

Ethyl 3-bromobenzoate (2.0 g, 8.7 mmol), hexabutylditin (5.51 ml, 10.9 mmol), tetrakis(triphenylphosphine)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 was heated to boiling under reflux for 72 h in an argon atmosphere. The solvent was removed under reduced pressure and the residue was purified column chromatography on silica gel (eluent:hexane). Named in the title compound was obtained as a colourless oil (1.1 g, 30%).

b) Methyl (1RS,2SR,3RS)-3-[2-(3-carbomethoxybiphenyl)-4 - methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2 - carboxylate.

Methyl (1RS, 2SR, 3RS)-3-(4-methoxy-2-trifluromethanesulfonate)- 1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-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-three(butyl-1-yl)stannyl benzoate (0.253 g, 0.58 mmol) mixed in dry dimethylformamide (5 ml) and heated to boiling under reflux for 24 hours the Product was filtered through celite and the celite was washed ethyl acetate. The combined filtrate was evaporated under reduced pressure and the method TCX been shown to be a hundred he is a mixture of the active ingredient is 2-(buta-1-yl)-4 - methoxyphenyl)-1-(3,4-methylenedioxyphenyl) -5-(prop-1-yloxy)indan-2-carboxylate (0.038 g), which was obtained as a colorless oil. Named in the title compound represented more polar component (0.08 g), which was still contaminated with the remnants of the tin (TMR) and was used without further purification.

c) (2RS, 2SR, 3RS)-3-[2-Carboxyphenyl)-4-methoxyphenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid.

Methyl (1RS, 2SR, 3RS)-3-[2-(3-carbomethoxybiphenyl)-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylate (0.08 g, crude) was dissolved in propan-2-OLE (1 ml) and added aqueous sodium hydroxide (1M, 1 ml, 1 mmol). The mixture was heated to boiling under reflux for 12 hours, then cooled, diluted with water, acidified 3M-aqueous hydrochloric acid and was extracted with ethyl acetate (3x). The combined organic extract was purified column chromatography on silica gel (eluent: 30% EtOAc/hexane/ 5% AcOH) to get named in the title compound as a colourless solid (20 mg).

So pl. 257 - 268oC.

Example 55. (1RS,2SR,3SR)-3-[2-(Buta-1-yl)-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid, salt of dicyclohexylamine.

Methyl (1RS, 2SR,3SR)-3-[2-(buta-1-yl)-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl) the sodium, (1 M, 0.75 ml, 0.75 mmol). The mixture was heated to boiling under reflux for 12 h and then cooled, diluted with water, acidified 3M-aqueous hydrochloric acid and was extracted with ethyl acetate (3x). The combined organic extract was purified column chromatography on silica gel (eluent: 30% EtOAc/hexane, then 30% EtOAc hexane/ 5% AcOH). The transformation of the product into its salt with dicyclohexylamine gave a named connection.

So pl. 179 - 182oC.

Anal. CaIc. C41H53NO8: C, 71.59; H, 7.77; N, 2.04.

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

Example 56. (1RS,2SR,3SR)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

a) Methyl (1RS,2RS,3SR)-3-(4-methoxy-2-phenylphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylat.

To a suspension of anhydrous LiCl (46 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium (0) (24 mg, 0.02 mmol) in dry dioxane (3 ml) was added a solution of methyl (1RS,2RS,3RS)-3-(4-Methoxy - 2-trifluromethanesulfonate)-1-(3,4-methylenedioxyphenyl)-5- (prop-1-yloxy)indan-2-carboxylate (95 mg, 0.16 mmol) and three(buta-1-yl)stannylene (319 mg, 0.87 mmol) in dioxane (1 ml). The mixture was heated to boiling under reflux in an argon atmosphere for 17 h, cooled to room temporaneously layer was dried (MgSO4anhydrous), filtered through a small column of silica gel and concentrated under reduced pressure to obtain oil. The product was purified instant column chromatography (silica gel, gradient elution from hexane to 10% ethyl acetate/hexane) to obtain the titled compound as a white solid (92 mg, 86%).

b) (1RS, 2SR, 3SR)-3-(4-Methoxy-2-phenylphenyl)-1-(3-4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

To a solution of methyl (1RS,2RS,3SR)-3-(4-methoxy-2-phenylphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylate (80 mg, 0.12 mmol) in dioxane (2 ml) was added 1M aqueous NaOH (0.3 ml, 0.3 mmol). The resulting mixture was heated to boiling under reflux for 48 hours. Then concentrated under reduced pressure. The residue was distributed between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4anhydrous). The solvent was removed under reduced pressure and the residue was purified instant column chromatography (silica gel, 20% ethyl acetate/hexane containing 5% acetic acid) to obtain named the title compound (36 mg, 46%).

So pl. 199 - 200oC.

1H NMR (B>); 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. CaIc. C33H30O63/4 H2O: C, 73.93; H, 5.90. Found: C, 74.12; H, 5.80.

Example 57. (1RS,2SR,3SR)-3-[2-[(E)-2-Carboxylate-1-yl]-4 - methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2 - carboxylic acid.

a) Methyl (1RS,2SR,3SR)-3-[2-[(E)-2-carbomethoxy-ethen-1-yl]-4 - methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2 - carboxylate.

1,3-bis(Diphenylphosphino)propane (0.066 mmol), Tris(dibenzylideneacetone)dipalladium (0) (24 mg, 0.026 mmol) and bis(triphenylphosphine)palladium (II) chloride (18 mg, 0.026 mmol) was dissolved in 4: 1 mixture of triethylamine/acetonitrile (5 ml) in an argon atmosphere. After 10 min at room temperature a solution of methyl (1RS,2SR,3RS)-3-(4-methoxy-2-trifluromethanesulfonate)-1- (3,4 methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylate (160 mg, 0.26 mmol) and methyl acrylate (679 mg, 7.89 mmol) was added to the above solvent mixture (3 ml). The reaction mixture was heated to boiling under reflux in an argon atmosphere for 20 h, cooled to room temperature and a small aliquot of the sample was analyzed by the method of the PMR, which showed that DMF (5 ml). The reaction mixture was heated to boiling under reflux overnight. Upon cooling the solution was filtered through a column of silica gel and concentrated to obtain oil. The crude product was purified instant column chromatography (silica gel, gradient elution from 10% to 20% ethyl acetate/hexane) to obtain named the title compound as a reddish brown solid (87 mg, 62%).

1H NMR (CDCl3): 8.17 (d, 1H, J=15.7 HZ); 7.44 (d, 1H, J=8.7 HZ); 7.11-7.07 (m, 2H); 6.90-6.70 (m, 6H); 6.42 (d, 1H, J=15.7 HZ); 5.94 (bs, 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).

b) (1RS, 2SR, 3SR)-3-[2-(E)-2-Carboxylate-1-yl] -4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

To a solution of methyl (1RS,2SR,3SR)-3-[2-[(E)-2-carbomethoxyamino-1 - yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylate (80 mg, 0.15 mmol) in dioxane (2 ml) was added 1H NaOH (0.5 ml, 0.5 mmol). The resulting mixture was heated to boiling under reflux for 3 h, then cooled and concentrated under reduced pressure. The residue is distributed between Ramstoremall removed under reduced pressure and named in the title compound was obtained as a white solid (73 mg, 96%).

1H NMR (CDCl3): 8.32 (d, 1H, J=15.6 HZ); 7.24-6.55 (m, 9H); 6.29 (d, 1H, J= 15.6 HZ); 5,94 (bs, 2H); 5.18 (d, 1H, J=9.9 HZ); 4.69 (d, 1H, J=9.9 HZ); 3.85 (S, 3H); 3.84 (t, 2H, J=6.9 HZ); 2.94 (dd, 1H, J=9.9, 9.9 HZ); 1.79 (sextet, 2H, J=6.9 HZ); 1.00 (t, 3H, J=6.9 HZ).

MS m/e 517(M+H)+].

Abal. CaIc. C30H28O8: C, 69.76; H, 5.46.

Found : C, 69.73; H, 5.26.

Example 58. (1RS,2SR,3SR)-3-[2-(2-Carboxylat-1-yl)-4 - methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2 - carboxylic acid

To a solution of (1RS,2SR,3SR)-3-[2-[(E)-2-carboxylate-1-yl]- 4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2 - carboxylic acid (43 mg, 0.08 mmol) in ethanol (40 mg) was added 10% palladium on activated carbon (40 mg). The resulting suspension was stirred overnight in an argon atmosphere, and then was filtered through a layer of celite. The filtrate was concentrated under reduced pressure to obtain named the title compound (35 mg, 82%) as a white solid.

1H NMR (CDCl3): 6.99 (d, 1H, J=8.6 HZ); 6.78-6.66 (m, 7H); 6.23 (bs, 1H); 5.88-5.87 (m, 2H); 4.88 (d, 1H, J=9.7 HZ); 4.54 (d, 1H, J=9.7 HZ); 3.72 (S, 3H); 3.70 (t, 2H, J=7 HZ); 2.98-2.90 (m, 1H); 2.68-2.51 (m, 2H); 1.65 (sextet, 2H, J=7.0 HZ); 0.89 (t, 3H, J=7.0 HZ).

MS (exact mass) M+: 518.1930 the existing connection.

Example 59. (1RS, 2SR, 3RS)-3-(2-Carboxymethylthio-4-methoxyphenyl) -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

So pl. 242 - 246oC (decomp.)

Example 60. (1RS, 2SR, 3SR)-3-[4-Methoxy-2-(prop-2-EN-1-yl)phenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

So pl. 126 - 127oC.

(exact mass) M+: 486.2021 ( = +2,1 mDA for C30H30O6)

Example 61. (1RS, 2SR,3SR)-3-[4-Methoxy-2-(prop-1-yl)phenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

So pl. 155 - 156oC.

Anal. CaIc. C30H32O6: C, 73.75; H, 6.60

Found : C, 73.45; H, 6.43

Example 62. (1RS,2SR,3RS)-3-[2-Carboxy-A-methoxyphenyl]-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

Anal. CaIc. C28H26O8: C, 68.56; H, 5.34.

Found : C, At 68.61; H, 5.58.

Example 63. (1RS, 2SR, 3SR)-3-[2-(2-Hydroxyethyl)-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

(exact mass) M+: 490.1994 ( = +0.3 mDA for C29H30O7).

Example 64. (1RS,2SR,3SR)-3-(2-Carboxymethyl-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

(exact mass) M+: 504.1788 ( = -0.4 mDA for C29H28yloxy)-indan-2 - carboxylic acid

MS (exact mass) M+: 504.2143 ( = +0.5 mDA C30H32O7).

Example 66. (1RS,2SR,3SR)-5-(4-Carboxyphenyl)-1,3-bis(3,4 - methylenedioxyphenyl)-1-indan-2-carboxylic acid.

So pl. 230 - 231oC.

Example 67. (1RS,2SR,3SR)-5-(4-Benzyloxyphenyl)-1,3-bis(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid

So pl. 105 - 106oC.

Example 68. (1RS,2SR,3SR)-5-([4-Hydroxyphenyl)-1,3-bis(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid

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

Example 69. (TRANS,TRANS-1,3,5-Tris(3,4-Methylenedioxyphenyl)- indan-2-carboxylic acid.

Anal. CaIc. C31H22O85/8 H2O: C, 69.76; H, 4.39.

Found : C, 69,81, H, 4,46.

Example 70. (1RS,3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan.

a) (1RS,3RS)-3-[(2-Methoxyethoxy)-4-methoxyphenyl)]-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan.

A solution of (1RS, 2SR, 3RS)-3-2-(methoxyethoxy)-4-methoxyphenyl-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid (0.2 g, 0.39 mmol) in dichloromethane (4 ml) and pyridine (28 μl, 1.6 mmol) was cooled to 0oC in argon atmosphere. To the solution was added thionyl chloride (60 μl, 0.8 mmol). Mixture allowed to warm to ambient temperature for 20 min, leucaenia (twice). The residue was dissolved in dichloromethane (4 ml) and was added triethylamine (250 μl). To this solution at room temperature in an argon atmosphere was added 2-mercaptopyridine (120 mg, 0.8 mmol) dissolved in dichloromethane (1 ml). After stirring for 20 min at room temperature was added t-butyltin (450 μl, 4 mmol) and the mixture was irradiated for 20 min (150 watt spot light source). Volatile products were removed under reduced pressure and the product was distributed between ethyl acetate and 3 M aqueous HCl. The organic extract was washed with water, us. aq. a solution of NaHCO3and finally the salt solution. After drying (MgSO4anhydrous) product filtered and evaporated. Purification of column chromatography gave named the title compound (0.075 g, 41%).

1H NMR (CDCl3): 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); of 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 points (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) (1RS, 3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan.

To a solution of (1RS,3RS)-3-(2-methoxyethoxy)-4-ketoximes was heated to boiling under reflux for 1.5 h in an argon atmosphere. The solvent was removed under reduced pressure and the product was distributed between EtOAc and water. The organic extract was washed with water, then saturated aqueous NaHCO3and finally the salt solution. After drying (MgSO4anhydrous) filtration and evaporation gave named the title compound (0,064 g, 94%).

1H NMR (CDCl3): 7.11 (d, 1H, J=8.4 HZ); 6.87 (d, 1H, J=7.8 HZ); 6.77-6.74 (4H, m); 6.61 (br S, 1H); 6.50 (dd, 1H, J=8.4, 2.5 HZ), 6.42 (d, 1H, J=2.5 HZ); 5.94 (d, 1H, J=1.2 HZ); 5.93 (d, 1H, J=1.2 HZ); 4.74 (S, 1H), 4.43 (dd, 1H, J=10.4, 7.6 HZ), 4.20 (dd, 1H, J=10.7, 7.3 HZ), 3.82 (t, 2H, J= 6.7 HZ), 3.79 (S, 3H), 2.89-2.82 (m, 1H), 2.15-2.08 (m, 1H), 1.77-1.71 (sextet, 2H, J=7.2 HZ), 0.99 (t, 3H, J=2.5 HZ).

MS (exact mass) M+Found : 418.1782 ( -0.2 mDA for C26H26O5).

Example 71. (1RS, 2RS)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan.

To a suspension of sodium hydride (5 mg, 0.21 mmol) in dimethylformamide (0.5 ml) was added (1RS, 3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan (0,058 g, 0.14 mmol) at a temperature of an ice bath in an argon atmosphere. After stirring for 15 min was added ethyl bromoacetate (50 ál, 0.2 mmol) and the solution was stirred for 1 h at room temperature. PR is th water NaHC3and finally the salt solution. After drying (MgSO4, anhydrous) filtration and evaporation followed by chromatography gave (1RS,3RS)-3-(2-carbomethoxy-4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)-5-(prop-1-yloxy)indan level (0.041 g). The product was dissolved in hot ethanol (10 ml) and added 1 M aqueous NaOH. The mixture was heated to boiling under reflux for 1 h, then cooled, acidified 6M aqueous HCl and was extracted with ethyl acetate. After evaporation the residue was led from ethyl acetate/hexane to obtain named the title compound (0.035 g, 93%).

So pl. 177 - 178oC.

1H NMR (CDCl3): 7.18 (d, 1H, J=8.5 HZ), 6.87 (d, 1H, J=8.4 HZ), 6.88-6.71 (4H, m), 6.56 (dd, 1H, J=8.4, 2.3 HZ), 6.53 (br.S, 1H), 6.41 (d, 1H, J= 2,3 HZ), 5,91 (br, S, 2H), 4.68-4.60 (m, 3H), 4.61 (dd, 1H, J=10.7, 7.2 HZ), 3.83-3.80 (m, 2H), 3.81 (S, 3H), 2.86 (dt, 1H, J=12.4, 7.2 HZ), 2.10-1.98 (m, 1H), 1.73 (sextet, 2H, J=7.2 HZ), 0.98 (t, 3H, J=7.4 HZ). MS (exact mass) M+= 476.1829 ( = +0.6 to mDA for C28H28O7).

Examples 72 - 84. According to the above procedures the following compounds.

(1RS, 2SR, 3SR)-1-(4-Methoxyphenyl)-3-(3,4,5 - trimethoxyphenyl)indan-2-carboxylic acid;

(1RS, 2SR,3SR)-1-(4-Ethoxyphenyl)-3-(3,4-methylenedioxyphenyl)indan - 2-carboxylic acid;

(1RS,2SR,3SR)-5-Carboxy-1,3 is) -5-(prop-2-enyloxy)indan-2-carboxylic acid;

(1RS, 2SR, 3RS)-3-(2,4-Acid)-5-hydroxy-1-(3,4 - methylenedioxyphenyl)-indan-2-carboxylic acid;

(1RS,2SR,3SR)-3-5-(2,3-Dihydro)-benzofuran-5-hydroxy-1- (3,4-methylenedioxyphenyl)-indan-2-carboxylic acid;

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

(1RS,2SR,3SR)-1-5-(2,3-Dihydrobenzofuranyl-1-(4-methoxyphenyl) indan-2-carboxylic acid;

(1RS, 2SR, 3RS)-1-3,4-(1,2-Ethylenedioxy)phenyl-3-(4-methoxyphenyl) indan-2-carboxylic acid;

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

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

(1RS, 2SR, 3SR)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxyphenyl) -5-(prop-1-yloxy)indan-2-carboxylic acid;

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

Example 85. Compositions for pharmaceutical use, comprising the compounds of this invention can be prepared in various forms and with numerous fillings. Examples of such compounds are shown below.

Formulations for inhalation.

The compound of formula I (from 1 to 100 mg) is sprayed from otmeraut - Pills

1. Active ingredient (Conn. forms. I) - 40

2. Corn starch - 20

3. Alginic acid - 20

4. Sodium alginate - 20

5. Mg-stearate - 1.3 - 2.3

Method of preparation tablets.

Step 1: Mix ingredients N 1 - 4 in a suitable mixer/blender.

Stage 2: To the mixture from stage I add enough water portions with thorough mixing after each addition. Such addition of water and stirring is continued until such time as the concentration of mass will allow you to turn it in moist pellets.

Stage 3: Critical mass is transformed into granules by passing it through a vibrating granulator, using a filter M 8 mesh. (2.38 mm).

Stage 4: the Wet granules are then dried in a drying Cabinet at 140oC (60oC) to dryness.

Stage 5: In the dry granules are injected lubricating ingredient N 5.

Stage 6: the Lubricated granules are compressed on the appropriate media for tablets.

Parenteral composition.

Pharmaceutical composition for parenteral administration is prepared by dissolving appropriate amounts of the compounds of formula 1 in polyethylene glycol under heating. This solution resbalar and sealed in sterile containers.

1. The compound of formula (I)

< / BR>
where R1is - X - (CH2)nAr or-X - (CH2)nR8;

R2- Ar;

P1is - X - (CH2)nR8;

P2is - X - (CH2)nR8;

R3and R5independently is hydrogen, R11, OH, C1-8-alkoxy, S(O)R11, - XR9- Y, or-X - (CH2)nR8where the methylene group-X - (CH2)nR8can be unsubstituted or substituted by one or more -(CH2)nAr groups;

R4is hydrogen;

R11- OH, or C1-5-alkoxy, which may be unsubstituted or substituted by a methoxy group;

R6is hydrogen or C1- C4-alkyl;

R7is hydrogen, C1- C6-alkyl and (CH2)nAr;

R8is CO2H or tetrazol, R11or R7;

R9- mono - or divalently C2- C10alkenyl or phenyl, each of which can be unsubstituted or substituted by one or more OH or COOH;

R10is R3or R4;

R11- mono - or divalently C2- C8alkenyl or C2- C8-quinil, which can be unsubstituted or substituted by one or more OH, or R
< / BR>
pyridyl, tetrazolyl, which can be unsubstituted or substituted by one or more R3or R4groups;

A - [C(R6)Z]m;

B - -CH2- or-O-;

Z1and Z2independently is hydrogen, OH, C1-8-alkoxy, N(R6)Z, NHCOR6, phenyl, benzyl or C2- C8-quinil, which may be independently substituted by COOH or OH, or Z1and Z2together may be-O-A-O on adjacent carbon atoms;

q = 0 or 1;

n = 0;

m = 1, 2, or 3;

the dotted line indicates the optional presence of a double bond,

or their pharmaceutically acceptable salt,

provided that (a) R2is not hydrogen when X is - S(O)qb) when the optional double bond is present, there is only one R10and there is no P1; (C) a compound of formula I is not (1RS) 1,3-diphenylene-2-carboxylic acid (CIS, CIS)-(1RS, 3SR)-1,3-diphenyl-indan-2-carboxylic acid, and (1RS)-3[3-methyl-1-phenyl-1 (H)-ind-2-EN-1-yl]propionic acid; (1RS)-2-[1,3-diphenyl-(1H)-ind-2-EN-2-yl] ethanoic acid; 1,3-diphenyl-1-amoxiillin-2-carboxylic acid; 1,2,3-trivinylbenzene, 1,3-diphenylbenzene; 1-(2,3-dimethyl-2-butene-1-yl)-1,3-diphenylbenzene; 1,3-diphenyl-methylindene; 1,3-diphenyl-2-methylindene; 1C(3,4-acid)-5,6-dimethoxyindole; 1,3-diphenyl-2-methoxyimino; 1,3-diphenyl-2-ethoxyethanol; 5-fluoro-2-methyl-inden-3-acetic acid.

2. Connection on p. 1, where R1- -X - (CH2)nAr, R2is a fragment of the formula (a) or (b), R3and R5independently is hydrogen, OH, C1-8-alkoxy, pyridyl, phenyl, R4is hydrogen, OH, C1-5-alkoxy, Z1and Z2independently - benzyl, hydrogen, OH, C1-5-alkoxy, - N(R6)Z, NCOR6or Z1and Z2together may be-O-A-O on contiguous carbons; P1and P2independently - hydrogen, CO2H or tetrazol, Ar - fragment of the formula (a) or (b) phenyl or pyridyl and X is -(CH2)n.

3. Connection on p. 2, where R3- hydrogen, -X - (CH2)nR8, R4and R5independently is hydrogen, OH, C1-5-alkoxy, C1-3-alkyl, P2is hydrogen, Z1is hydrogen and Z2is hydrogen, OH, C1-5-alkoxy, NH2, benzyl or NH(CO)CH3or Z1and Z2together may be-O-A-O on adjacent carbon atoms.

4. Connection on p. 3, where R1a fragment of the formula (b) and R2a fragment of the formula (a) or (b), A - CH2B is-O-, there is no optional double bond, R1and XR2are in the TRANS position in relation to P1, Z> is hydrogen or C1-2-alkoxy, P2, R5and R10- hydrogen.

5. Connection on p. 1, selected from the group comprising the following compounds: (1RS, 2SR, 3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indan-2-carboxylic acid; (1RS, 2RS, 3SR)-5-hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indan-2-carboxylic acid; (1RS, 2RS, 3SR)-5-methoxy-3-(4-methoxyphenyl)1-(3,4-methylenedioxyphenyl)indan-2-carboxylic acid; (1RS, 2SR, 3SR)-1,3-bis(3,4-methylenedioxyphenyl)-5,5-hydroxy-indan-2-carboxylic acid; (1RS, 2SR, 3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid; (1RS, 2SR, 3RS)- 3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid; (1RS, 2SR, 3SR)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(2-methoxy-4,5-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid; (1RS, 2SR, 3RS)-3-[2-(1-carboxylat-2-yloxy)-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid, salt of bis-dicyclohexylamine; (1RS, 2SR, 3SR)-3-[2- [(E)-2-carboxylate-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid (1RS, 2SR, 3SR)-3-[2-(2-carboxylat-1-yl)-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indan-2-carboxylic acid, (1RSP CLASS="ptx2">

6. The compound according to any one of paragraphs.1 to 5 showing the properties of the antagonist endothelioma receptors.

7. The compound according to any one of paragraphs.1 - 6, block endothelioma receptors.

8. Pharmaceutical composition having the property antagonist endothelioma receptors, characterized in that it comprises a compound according to any one of paragraphs.1 to 5 in an effective amount and a pharmaceutically acceptable carrier.

9. The method of suppressing endothelioma receptors, including the appointment of the needy in this subject an effective amount of a compound according to any one of paragraphs.1 - 5.

10. The method of obtaining the compounds of formula (I) under item 1 or its pharmaceutically acceptable salt, namely, that includes the interaction of the compounds of formula (II)

< / BR>
where Z1Z2and R1such as in point 1, or a group, turn in them;

X is alkyl,

with magnetogenesis compound of formula (III)

R2- (CH2)n- MgBr,

where R2such as in point 1, or a group, turn it,

in a suitable solvent to obtain compounds of formula (IV)

< / BR>
which restore and thereafter if desired or necessary, is subjected to the conversion of R1, R2

 

Same patents:

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to the production of tetrazole following General formula (I) or its pharmacologically acceptable salt

The invention relates to the derivatives of tetrazole exhibiting inhibitory alsoreported activity, the method of production thereof and to compositions containing the derivative tetrazole as an effective component

The invention relates to the synthesis of heterocyclic compounds, and in particular to an improved process for the preparation of substituted 1(2)-benzyl-5-R-tetrazoles General formula I

Rwhere(A)< / BR>
R = phenyl, R1= A, R = 4-OCH3-phenyl, R1= A;

R = 3,4 - (OCH3)2-phenyl, R1= A; R = 3-pyridyl, R1= A;

R = 4-pyridyl, R1= A; R = 4-Cl-phenyl, R1= A;

R = 4-Br-phenyl, R1= A; R = NH2, R1= A;

R = N-phthalimido, R1= A; R = phenyl, R1= B;

R = 4-OCH3-phenyl, R1= B; R = 3,4-(OCH3)2-phenyl, R1= B;

R = 4-Br-phenyl, R1= B; R = 4-NO2-phenyl, R1= B

The invention relates to the synthesis of heterocyclic poliittisten compounds and can be used to obtain tetrazole in process variant
The invention relates to the field of cosmetology and medicine and can be used for the production of medical-cosmetic products such as creams, ointments, emulsions, lotions, used in the treatment and prevention of diseases of the musculoskeletal system and the nervous system
The invention relates to medicine, in particular to cancer, and can be used in the treatment of locally common forms of lung cancer

The invention relates to pharmaceutical industry and relates to a solid pharmaceutical composition risedronate for oral administration

The invention relates to ophthalmology and is intended for the treatment of hemorrhages in the internal environment and shell eyes

The invention relates to the field of medicine and cosmetics, in particular for external tools: creams, ointments, emulsions, gels, solutions used for treatment of various infections
The invention relates to a pharmaceutical preparation for oral administration, especially tablets, which as activitiesthese substance containing pharmacologically acceptable salt of dichlorodibenzofuran acid, i.e

The invention relates to methods build bones in humans and animals, that is, to the treatment of osteoporosis and related diseases
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