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(11) | EP 0 699 069 B9 |
| (12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
| Note: Bibliography reflects the latest situation |
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| (54) |
ENDOTHELIN RECEPTOR ANTAGONISTS ENDOTHELIN-REZEPTOR-ANTAGONISTEN ANTAGONISTES DES RECEPTEURS DE L'ENDOTHELINE |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
FIELD OF INVENTION
[0001] The present invention relates to novel indane and indene derivatives, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists.
[0002] Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms, ET-1, ET-2 and ET-3. [Unless otherwise stated "endothelin" shall mean any or all of the isoforms of endothelin]. Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.
[0003] In vivo, endothelin has pronounced effects on blood pressure and cardiac output. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in rats causes a transient, dose-related depressor response (lasting 0.5 to 2 minutes) followed by a sustained, dose-dependent rise in arterial blood pressure which can remain elevated for 2 to 3 hours following dosing. Doses above 3 nmol/kg in a rat often prove fatal.
[0004] Endothelin appears to produce a preferential effect in the renal vascular bed. It produces a marked, long-lasting decrease in renal blood flow, accompanied by a significant decrease in GFR, urine volume, urinary sodium and potassium excretion. Endothelin produces a sustained antinatriuretic effect, despite significant elevations in atrial natriuretic peptide. Endothelin also stimulates plasma renin activity. These findings suggest that ET is involved in the regulation of renal function and is involved in a variety of renal disorders including acute renal failure, cyclosporine nephrotoxicity, radio contrast induced renal failure and chronic renal failure.
[0005] Studies have shown that in vivo, the cerebral vasculature is highly sensitive to both the vasodilator and vasoconstrictor effects of endothelin. Therefore, ET may be an important mediator of cerebral vasospasm, a frequent and often fatal consequence of subarachnoid hemorrhage.
[0006] ET also exhibits direct central nervous system effects such as severe apnea and ischemic lesions which suggests that ET may contribute to the development of cerebral infarcts and neuronal death.
[0007] ET has also been implicated in myocardial ischemia (Nichols et al. Br. J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Circ. Res., 65: 1193- 1200, 1989) coronary vasospasm (Fukuda et al., Eur. J. Pharm. 165: 301-304, 1989 and Lüscher, Circ. 83: 701, 1991) heart failure, proliferation of vascular smooth muscle cells, (Takagi, Biochem & Biophys, Res. Commun.; 168: 537-543, 1990, Bobek et al., Am. J. Phvsiol. 258:408-C415, 1990) and atherosclerosis, (Nakaki et al., Biochem. & Biophys. Res. Commun. 158: 880-881, 1989, and Lerman et al., New Eng. J. of Med. 325: 997-1001, 1991). Increased levels of endothelin have been shown after coronary balloon angioplasty (Kadel et al., No. 2491 Circ. 82: 627, 1990).
[0008] Further, endothelin has been found to be a potent constrictor of isolated mammalian airway tissue including human bronchus (Uchida et al., Eur J. of Pharm. 154: 227-228 1988, LaGente, Clin. Exp. Allergy 20: 343-348, 1990; and Springall et al., Lancet, 337: 697-701, 1991). Endothelin may play a role in the pathogenesis of interstitial pulmonary fibrosis and associated pulmonary hypertension, Glard et al., Third International Conference on Endothelin, 1993, p. 34 and ARDS (Adult Respiratory Distress Syndrome), Sanai et al., Supra, p. 112.
[0009] Endothelin has been associated with the induction of hemorrhagic and necrotic damage in the gastric mucosa (Whittle et al., Br. J. Pharm. 95: 1011-1013, 1988); Raynaud's phenomenon, Cinniniello et al., Lancet 337: 114-115, 1991); Crohn's Disease and ulcerative colitis, Munch et al., Lancet, Vol. 339, p. 381; Migraine (Edmeads, Headache, Feb. 1991 p 127); Sepsis (Weitzberg et al., Circ. Shock 33: 222-227, 1991; Pittet et al., Ann. Surg. 213: 262-264, 1991), Cyclosporin-induced renal failure or hypertension (Eur. J. Pharmacol., 180: 191-192, 1990, Kidney Int, 37: 1487-1491, 1990) and endotoxin shock and other endotoxin induced diseases (Biochem. Biophys. Res. Commun., 161: 1220-1227, 1989, Acta Physiol. Scand. 137: 317-318, 1989) and inflammatory skin diseases. (Clin Res. 41:451 and 484, 1993).
[0010] Endothelin has also been implicated in preclampsia of pregnancy. Clark et al., Am. J. Obstet. Gynecol. March 1992, p. 962-968; Kamor et al., N. Eng. J. of Med., Nov 22, 1990, p. 1486-1487; Dekker et al., Eur J. Ob. and Gyn. and Rep. Bio. 40 (1991) 215-220; Schiff et al., Am. J. Ostet. Gynecol. Feb 1992, p. 624-628; diabetes mellitus, Takahashi et al., Diabetologia (1990) 33:306-310; and acute vascular rejection following kidney transplant, Watschinger et al., Transplantation Vol. 52, No. 4, pp. 743-746.
[0011] Endothelin stimulates both bone resorption and anabolism and may have a role in the coupling of bone remodeling. Tatrai et al. Endocrinology, Vol. 131, p. 603-607.
[0012] Endothelin has been reported to stimulate the transport of sperm in the uterine cavity, Casey et al., J. Clin. Endo and Metabolism, Vol. 74, No. 1, p. 223-225, therefore endothelin antagonists may be useful as male contraceptives. Endothelin modulates the ovarian/menstrual cycle, Kenegsberg, J. of Clin. Endo. and Met., Vol. 74, No. 1, p. 12, and may also play a role in the regulation of penile vascular tone in man, Lau et al., Asia Pacific J. of Pharm., 1991, 6:287-292 and Tejada et al., J. Amer. Physio. Soc. 1991, H1078-H1085. Endothelin also mediates a potent contraction of human prostatic smooth muscle, Langenstroer et al., J. Urology, Vol. 149, p. 495-499.
[0013] Thus, endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, renal failure, ischemia induced renal failure, sepsis-endotoxin induced renal failure, prophylaxis and/or treatment of radio-contrast induced renal failure, acute and chronic cyclosporin induced renal failure, cerebrovascular disease, myocardial ischemia, angina, heart failure, asthma, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin induced multiple organ failure or disseminated intravascular coagulation, cyclosporin-induced renal failure and as an adjunct in angioplasty for prevention of restenosis, diabetes, preclampsia of pregnancy, bone remodeling, kidney transplant, male contraceptives, infertility and priaprism and benign prostatic hypertrophy.
SUMMARY OF THE INVENTION
[0014] This invention comprises indane and indene derivatives represented by Formula (I) and pharmaceutical compositions containing these compounds, and their use as endothelin receptor antagonists which are useful in the treatment of a variety of cardiovascular and renal diseases including but not limited to:
stroke, cerebrovascular vasospasm, myocardial ischemia, angina, heart failure, atherosclerosis, and as an adjunct in angioplasty for prevention of restenosis.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The compounds of this invention are represented by structural Formula (I):
wherein:
R1 is -X(CH2)nAr or -X(CH2)nR8 or
R2 is hydrogen, Ar, C1-4alkyl or (c);
P1 is -X(CH2)nR8;
P2 is -X(CH2)nR8 or -X-R9-Y;
R3 and R5 are independently hydrogen, R11, OH, C1-8alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, R11CO2R7, -X-R9-Y or -X(CH2)nR8 wherein each methylene group within -X(CH2)nR8 may be unsubstituted or substituted by one or two -(CH2)nAr groups;
R4 is hydrogen, R11, OH, C1-5alkoxy, S(O)qR11, N(R6)2, -X(R11), Br, F, I, Cl or NHCOR6 wherein the C1-5alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
R6 is independently hydrogen or C1-4alkyl;
R7 is independently hydrogen, C1-10alkyl, C2-10alkenyl or C2-8alkynyl all of which may be unsubstituted or substituted by one or more OH, N(R6)2, CO2R12, halogen or XC1-5alkyl or R7 is (CH2)nAr;
R8 is hydrogen, R11, CO2R7, CO2C(R11)2 O(CO)XR7, PO3(R7)2, SO2NR7R11, NR7SO2R11, CONR7SO2R11, SO3R7, SO2R7, P(O)(OR7)R7, CN, -CO2(CH2)mC(O)N(R6)2, C(R11)2N(R7)2, C(O)N(R6)2, tetrazole or OR6;
R9 is (CH2)n, divalent C1-10alkyl, divalent C2-10alkenyl or phenyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, COOH, halogen, or R9 may be 〉C=O or XC1-5alkyl;
R10 is R3 or R4;
R11 is hydrogen, Ar, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen; with the proviso that when R11 is present in the group R11CO2R7, R11 is not hydrogen.
R12 is hydrogen, C1-6alkyl, C2-6alkenyl or C2-7alkynyl;
X is (CH2)n, O, NR6 or S(O)q;
Y is CH3 or X(CH2)nAr;
Ar is:
naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more R3 or R4 groups;
A is C=O, or [C(R6)2]m;
B is -CH2- or -O-;
Z1 and Z2 are independently hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, OH, C1-8alkoxy, S(O)qC1-8alkyl, N(R6)2, Br, F, I, Cl, NHCOR6, -X-R9-Y, -X(CH2)nR8, phenyl, benzyl or C3-6cycloalkyl wherein the C1-8alkyl, C2-8alkenyl or C2-8alkynyl may be optionally substituted by COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2, or halogen; or Z1 and Z2 together may be -O-A-O- on contiguous carbons;
Z3 is Z1 or -X-R9-Y;
q is zero, one or two;
n is an integer from 0 to six;
m is 1, 2 or 3; and the dotted line indicates the optional presence of a double bond; or a pharmaceutically acceptable salt thereof; provided that
· R2 is not hydrogen when X is S(O)q;
· R1 and R7 are not hydrogen when q is 1 or 2 in S(O)qR11 or S(O)qR7;
· when the optional double bond is present there is only one R10 and there is no P1 and P2 is not NR6R9Y;
· when the optional double bond is present in Formula (I) and X-R2 is attached to the double bond, X is not NR6;
· when the optional double bond is present and R1 is attached directly to the double bond, R1 is not NR6Ar;
· when R3, R5, Z1, Z2, or Z3 is X(CH2)nR8 and n is not 0, X is oxygen or NR6 when R8 is OR6 or CO2H;
· when R8 is CO2C(R11)2O(CO)XR7, X is not S(O)q;
· the compound of Formula I is not methyl 1,3-diphenylindene-2-carboxylate; ethyl 1,3-diphenylindene-2-carboxylate; 1,3-diphenyl-2-cyanoindene; or ethyl 1,3-diphenyl-3-hydroxyindane-2-carboxylate;
and further provided that compounds wherein:R1 is -X(CH2)nAr or -X(CH2)nR8 or
R2 is hydrogen, Ar or (c);
P1 is -X(CH2)nR8;
P2 is -X(CH2)nR8, or -XR9Y;
R3 and R5 are independently hydrogen, R11, OH, C1-8alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, -XR9-Y or -X(CH2)nR8 wherein the methylene groups of -X(CH2)nR8 may be unsubstituted or substituted by one or more -(CH2)nAr groups;
R4 is hydrogen, R11, OH, C1-5alkoxy, S(O)qR11, N(R6)2, -X(R11), Br, F, I, Cl or NHCOR6 wherein the C1-5alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
R6 is independently hydrogen or C1-4alkyl;
R7 is independently hydrogen, C1-6alkyl or (CH2)nAr;
R8 is hydrogen, R11, CO2H, PO3H2, P(O)(OH)R7 or tetrazole;
R9 is C1-10alkyl, C2-10alkenyl or phenyl all of which may be unsubstituted or substituted by one or more OH, N(R6)2, COOH, halogen or XC1-5alkyl;
R10 is R3 or R4;
R11 is C1-8alkyl, C2-8alkenyl, C2-8alkynyl all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen;
X is (CH2)n, O, NR6 or S(O)q;
Y is CH3 or -CH2X(CH2)nAr;
Ar is:
naphthyl, indolyl, pyridyl or thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more R3 or R4 groups;
A is C=O, or [C(R6)2]m;
B is -CH2- or -O-;
Z1 and Z2 are independently hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, OH, C1-8alkoxy, S(O)qC1-8alkyl, N(R6)2, Br, F, I, Cl, NHCOR6,
-X(CH2)nR8, phenyl, benzyl or C3-6cycloalkyl wherein the C1-8alkyl, C2-8alkenyl or C2-8alkynyl may be optionally substituted by COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2, or halogen; or Z1 and Z2 together may be -O-A-O- on contiguous carbons;
Z3 is Z1 or XR9Y;
q is zero, one or two;
n is an integer from 0 to six;
m is 1, 2 or 3; are excluded.
[0017] All alkyl, alkenyl, alkynyl and alkoxy groups may be straight or branched. The term "halogen" is used to mean iodo, fluoro, chloro or bromo. Alkyl groups may be substituted by one or more halogens up to perhalogenation.
[0018] The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and diastereoisomers are contemplated to be within the scope of the present invention.
[0019] Preferred compounds are those wherein R1 is X(CH2)nAr, (Ar is (a) or (b)), dihydrobenzofuranyl, benzodioxanyl, cyclohexyl, C1-4alkyl; R2 is (a), (b) C1-4alkyl, indolyl or hydrogen; R3 and R5 are independently hydrogen, OH, C1-5alkoxy, halogen, -OC1-4alkyl phenyl, R11CO2R7, C1-4alkyl, N(R6)2, NH(CO)CH3, -X(CH2)nR8, -X-R9-Y, pyridyl, phenyl or S(O)pC1-5alkyl; R4 is hydrogen, OH, C1-5alkoxy, halogen, C1-4alkyl, N(R6)2, NH(CO)CH3 or S(O)pC1-5alkyl; Z1, Z2 and Z3 are independently XR9Y, benzyl, hydrogen, OH, C1-5alkoxy, -N(R6)2, S(O)qC1-8alkyl, NHCOR6, X(CH2)nR8 or halogen, or Z1 and Z2 together may be -O-A-O- on contiguous carbons; P1 and P2 are independently hydrogen, CO2H or tetrazole; Ar is (a), (b) or pyridyl; X is (CH2)n or oxygen.
[0020] More preferred are compounds wherein R3 is hydrogen, -X(CH2)nR8 or R11CO2R7; R4 and R5 are independently hydrogen, OH, C1-5alkoxy, SC1-5alkyl, a moiety of formula (a), F, Br, C1-3alkyl or NH2; Z1 and Z3 are hydrogen and Z2 is hydrogen, OH, C1-5alkoxy, halogen, X(CH2)nR8, NH2, benzyl, NH(CO)CH3, or Z1 and Z2 together may be O-A-O.
[0021] Most preferred are compounds wherein R1 is (b) and R2 is (a) or (b); A is CH2, B is -O-; there is no optional double bond; R1 and XR2 are trans to P1; Z2 is OH, C1-5alkoxy, -OCH2CHCH2 or hydrogen, Z1 is hydrogen; R3 is XAr, hydrogen, X(CH2)qCOOH, X(CH2)qCONR7SO2R11 or CH=CHCO2H, R4 is hydrogen, a moiety of formula (a) or C1-2alkoxy; and R5, R10 and P2 are hydrogen.
[0022] Also included are the following compounds:
(+) (1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid;
(1RS, 2SR, 3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4- methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt;
(+) (1S, 2R, 3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, dicyclohexylamine salt;
(1S, 2R, 3S)-3-[(2,2-dimethylpropanoyloxymethoxycarbonylmethoxy)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt.
[0023] The present invention provides compounds of Formula (I) above
which can be prepared by a process which comprises:
a) reacting a compound of Formula (2) wherein X is C1-5alkyl
with a substituted benzaldehyde or aldehyde of Formula (3).
D-CHO (3)
wherein D is Ar or (c) as defined in Formula I, in a suitable solvent such as benzene
with a catalyst such as piperidinium acetate at reflux to provide a compound of Formula
(4).
Cyclization of compound (4) in the presence of a suitable Lewis acid such as titanium
tetracholoride or aluminum chloride or alternatively when Z1 is 3-OR (meta)(where R is C1-5alkyl, or benzyl), trifluoroacetic acid, provides an indanone of the Formula (5).
Dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an appropriate solvent
or alternatively bromination with pyridinium hydrobromide perbromide in dichloromethane
followed by treatment with 1,5-diazabicyclo[4,3,0]non-5-ene provides indenones of
Formula (6).
b) Alternatively, a compound of Formula 6 wherein Z1, Z2 and Z3 are hydrogen and
can be prepared by treatment of 2-bromobenzoic acid with two equivalents of n-butyllithium
in a solvent such as tetrahydrofuran under argon at -78°C followed by the addition
of an acid chloride of Formula (7):
provides a compound of Formula (8):
Treatment of compounds of type (8) with thionyl chloride at reflux gives an acid chloride
which can be isolated by concentration under reduced pressure. This acid chloride
can then be treated with diethyl magnesium malonate in a solvent such as ether to
give a compound of Formula (9):
Reaction of a compound of type (9) at reflux with 5% aqueous sodium carbonate gives
compounds of Formula (10):
c) Treatment of an indenone of Formula (11):
wherein Z1, Z2, Z3 and R1 are as defined for formula I or a group convertable to them, with an organomagnesium
compound of Formula (12) wherein R2 is defined for
R2(CH2)nMgBr (12)
Formula I or a group convertable to it, in a suitable solvent provides compounds of
Formula (13):
[0024] Saponification of compounds of Formula (13) using sodium hydroxide in aqueous methanol followed by reduction with triethylsilane and boron trifluoride etherate in a suitable solvent such as dichloromethane at 0°C affords racemic compounds of Formula (14).
Conjugate addition of nucleophiles to an ester derived from Formula (14), followed by saponification affords compounds of Formula (I) having an R10 other than hydrogen. Re-introduction of a double bond into an ester derived from such acids followed by conjugate addition of another nucleophilic species and subsequent saponification affords compounds of Formula (1) in which neither R10 substituent is hydrogen.
[0025] Reduction of compounds of Formula (13) with triethylsilane and boron trifluoride etherate in a suitable solvent such as dichloromethane at 0°C followed by hydrogenation with hydrogen gas under pressure at approximately 60 psi in the presence of a suitable catalyst such as 10% palladium on charcoal affords compounds of Formula (15):
[0026] Alkylation or acylation of the ester enolate derived from Formula (15) affords compounds wherein P1 and P2 are as defined in Formula (1).
[0027] Alternatively, hydrogenation of compounds of Formula (13) with hydrogen gas under pressure at approximately 60 psi in the presence of a suitable catalyst such as 10% palladium on charcoal in a suitable solvent such as ethyl acetate or methanol containing 1-5% acetic acid affords compounds of Formula (15). Treatment of these compounds with a base such as sodium hydroxide in a suitable solvent such as aqueous ethanol provides racemic compounds of Formula (16):
wherein Z1, Z2 and Z3 are hydrogen; R1 = R2; and n is 0.
Treatment of compounds of Formula (13) with triethylsilane and boron trifluoride etherate in a suitable solvent such as dichloromethane at 0°C followed by reaction with samarium II iodide in a suitable solvent such as tetrahydrofuran and then saponification, provides compounds of Formula (17)
[0028] With appropriate manipulation and protection of any chemical functionalities, synthesis of the remaining compounds of the Formula (I) is accomplished by methods analogous to those above and to those described in the Experimental section.
[0029] In order to use a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
[0030] Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
[0031] Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
[0032] Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
[0033] Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
[0034] A typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
[0035] Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
[0036] Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
[0037] Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
[0038] The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
[0039] No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
[0040] The biological activity of the compounds of Formula (I) are demonstrated by the following tests:
I. Binding Assay
A) Membrane Preparation
[0041] Rat cerebellum or kidney cortex were rapidly dissected and frozen immediately in liquid nitrogen or used fresh. The tissues, 1-2 g for cerebellum or 3-5 g for kidney cortex, were homogenized in 15 mls of buffer containing 20mM Tris HCl and 5mM EDTA, pH 7.5 at 4°C using a motor-driven homogenizer. The homogenates were filtered through cheesecloth and centrifuged at 20,000 x g for 10 minutes at 4°C. The supernatant was removed and centrifuged at 40,000 xg for 30 minutes at 4°C. The resulting pellet was resuspended in a small volume of buffer containing 50 mM Tris, 10 mM MgCl2, pH 7.5; aliquotted with small vials and frozen in liquid nitrogen. The membranes were diluted to give 1 and 5 mg of protein for each tube for cerebellum and kidney cortex in the binding assay.
[0042] Freshly isolated rat mesenteric artery and collateral vascular bed were washed in ice cold saline (on ice) and lymph nodes were removed from along the major vessel. Then, the tissue was homogenized using a polytron in buffer containing 20 mM Tris and 5mM EDTA, pH 7.5 at 4°C in 15 ml volume for ∼6 gm of mesenteric artery bed. The homogenate was strained through cheesecloth and centrifuged at 2,000 xg for 10 min. at 4°C. The supernatant was removed and centrifuged at 40,000 xg for 30 min. at 4°C. The resulting pellet was resuspended as explained above for cerebellum and kidney cortex. Approximately 10 mg of membrane protein was used for each tube in binding experiments.
B) [125I]ET-1 Binding Protocol
[0043] [125I]ET-1 binding to membranes from rat cerebellum (2-5 mg protein/assay tube) or kidney cortex (3-8 mg protein/assay tube) were measured after 60 minutes incubation at 30°C in 50 mM Tris HCl, 10 mM MgCl2, 0.05% BSA, pH 7.5 buffer in a total volume of 100 ml. Membrane protein was added to tubes containing either buffer or indicated concentration of compounds. [125I]ET-1 (2200 Ci/mmol) was diluted in the same buffer containing BSA to give a final concentration of 0.2-0.5 nM ET-1. Total and nonspecific binding were measured in the absence and presence of 100 nM unlabelled ET-1. After the incubation, the reactions were stopped with 3.0 ml cold buffer containing 50 mM Tris and 10 mM MgCl2, pH 7.5. Membrane bound radioactivity was separated from free ligand by filtering through Whatman GF/C filter paper and washing the filters 5 times with 3 ml of cold buffer using a Brandel cell harvester. Filter papers were counted in a gamma counter with an efficiency of 75%. IC50's for the compounds of this invention range from 0.1 nm to 50 mm.
II. In Vitro Vascular Smooth Muscle Activity
[0044] Rat aorta are cleaned of connective tissue and adherent fat, and cut into ring segments approximately 3 to 4 mm in length. Vascular rings are suspended in organ bath chambers (10 ml) containing Krebs-bicarbonate solution of the following composition (millimolar): NaCl, 112.0; KCl, 4.7; KH2PO4, 1.2; MgSO4, 1.2; CaCl2, 2.5; NaHCO3, 25.0; and dextrose, 11.0. Tissue bath solutions are maintained at 37°C and aerated continuously with 95% 02/ 5% CO2. Resting tensions of aorta are maintained at 1 g and allowed to equilibrate for 2 hrs., during which time the bathing solution is changed every 15 to 20 min. Isometric tensions are recorded on Beckman R-611 dynographs with Grass FT03 force-displacement transducer. Cumulative concentration-response curves to ET-1 or other contractile agonists are constructed by the method of step-wise addition of the agonist. ET-1 concentrations are increased only after the previous concentration produces a steady-state contractile response. Only one concentration-response curve to ET-1 is generated in each tissue. ET receptor antagonists are added to paired tissues 30 min prior to the initiation of the concentration-response to contractile agonists.
[0045] ET-1 induced vascular contractions are expressed as a percentage of the response elicited by 60 mM KCl for each individual tissue which is determined at the beginning of each experiment. Data are expressed as the mean ± S.E.M. Dissociation constants (Kb) of competitive antagonists were determined by the standard method of Arunlakshana and Schild. The potency range for compounds of this invention range from 0.1 nM to 50 mm.
[0046] The following examples are illustrative and are not limiting of the compounds of this invention.
EXAMPLE 1
(+) (1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0047]
a) 3-(Prop-1-yloxy)acetophenone. To a slurry of NaH (13.84 g, 0.58 mol) in dry DMF (50 mL) at 0°C, was added a solution of 3-hydroxyacetophenone (50 g, 0.37 mol). After stirring for 30 min. 1-iodopropane (70 mL, 0.72 mol) was added and the mixture stirred overnight at room temperature. The mixture was diluted with dry DMF (50 mL) and further NaH (2.77 g, 0.12 mol) added followed by 1-iodopropane (23 mL, 0.24 mol). After 1 h. TLC indicated that the reaction was complete and the product was cautiously quenched with 6M HCl and extracted with EtOAc. The EtOAc extract was washed successively with H2O, 10% aqueous NaOH and then brine. After drying (MgSO4), filtration and evaporation gave the title compound (65 g, 98%) as a light yellow oil which was used without further purification. Anal. Calc. for C11 H14O2: C, 74.13; H, 7.89. Found: C, 73.85; H, 7.86.
b) Methyl 3-(Prop-1-yloxy)benzoylacetate. To a suspension of NaH (12 g, 0.5 mol) in dry dimethyl carbonate (50 mL) was added slowly a solution of 3-(Prop-1-yloxy)acetophenone (65 g, 0.37 mol) in dry dimethyl carbonate (100 mL). During the addition the exothermicity of the reaction caused refluxing. Following the addition the mixture was stirred mechanically overnight and was then quenched cautiously with 3M HCl and extracted with EtOAc. The EtOAc extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and brine. After drying (MgSO4), filtration and evaporation gave a yellow oil (82 g, quantitative) which was used without further purification.
c) Methyl 3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate.To a solution of methyl 3-(prop-1-yloxy)benzoylacetate (10 g, 4.2 mmol) in benzene (50 mL) was added 3,4-methylenedioxybenzaldehyde (6.36 g, 4.2 mmol) followed by piperidine (0.42 mL, 0.42 mmol) and glacial acetic acid (8 drops approx.). The mixture was refluxed for 2 h. and the volatiles removed in vacuo to give methyl 3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate (7.4 g, 48%) as an off white solid after trituration with methanol (m. p. 122-123°C). Anal. Calc. for C21 H20O6: C, 68.47; H, 5.47. Found: C, 68.81; H, 5.49.
d) Methyl (1RS,2SR)-1-(3,4-Methylenedioxyphenyl)-5-(prop-1-yloxy)-3-oxo-indane-2-carboxylate. Methyl 3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate (7.4 g, 2.0 mmol) was dissolved in trifluoroacetic acid (50 mL) at 0°C and the mixture stirred at room temperature for 20 min. The trifluoroacetic acid was removed in vacuo to give the title compound (6.4 g, 87 %) as a white solid after trituration with warm isopropanol m. p. 106-108°C. Anal. Calc. for C21 H20O6: C, 68.47; H, 5.47. Found: C, 68.12; H, 5.41.
e) Methyl 3-(3,4-Methylenedioxyphenyl)-6-(prop-1-yloxy)-1-oxo-indene-2-carboxylate. Methyl (1RS, 2SR)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-3-oxo-indane-2-carboxylate (26.2 g, 71 mmol) was dissolved in toluene (250 mL) and DDQ (dichlorodicyano-quinone) (16.5 g, 71 mmol) was added. The mixture was heated at 80°C for 2 h. then cooled, filtered and the solvent removed in vacuo. The product was purified by flash column chromatography on silica gel (eluant: EtOAc/hexane, 20:80) to give the title compound as an orange solid (11.3 g, 44 %); m.p. 125-126°C. Anal. Calc. for C21 H18O6: C, 68.85; H, 4.95. Found: C, 68.45; H, 4.97.
f) Methyl (1RS)-1-Hydroxy-1-(4-methoxy-2-methoxymethoxyphenyl)-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-carboxylate. To dry magnesium turnings (1.7 g, 69 mmol) under an argon atmosphere was added portionwise, a solution of 1-bromo-4-methoxy-2-methoxymethoxybenzene (16.8 g, 68 mmol) in 5% THF/ether (120 mL). The resulting 4-methoxy-2-methoxymethoxyphenyl magnesium bromide was added to a solution of methyl 3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)-1-oxo-indene-2-carboxylate (18.5 g, 51 mmol) in THF (400 mL) under an argon atmosphere at 0°C. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min. The mixture was partitioned between 3M HCl and EtOAc . The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue purified by flash chromatography on silica gel (eluant: EtOAc/hexane, 10-20%) to afford the title compound as a yellow oil (24.5 g, 91%). Anal. Calc. for C30H30O9: C, 67.41; H, 5.66;. Found: C, 67.21; H, 5.66.
SEPARATION
[0048] Separation of (+) and (-) methyl (1RS)-1-Hydroxy-1-(4-methoxy-2-methoxymethoxyphenyl)-3-(3,4-methylenedioxyphenyl)-6-(prop- 1-yloxy)indene-2-carboxylate was done on a column of cellulose tris(3,5-dimethylphenyl carbamate) coated on silica gel (Daicel Chiralcel OD); retention time for (+) 8.8 min. [α]25D= +87.5° (c = 0.24, CH3OH). Retention time for (-) 14.5 min. [α]25D= +85.9° (c = 0.21, CH3OH)
HPLC data: column Chiralcel OD (DAICEL) 21.2 mm internal diameter, 250 mm length; solvent Ethanol:Hexane 60:40; flow rate 10 mL/min.; injection: 1 g of racemate; detection UV = 405 nm
g) (+)Methyl (1S,2S,3S)-3-(4-Methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. A parr vessel was charged with (+) methyl (1RS)-1-Hydroxy-1-(4-methoxy-2-methoxymethoxyphenyl)-3-(3,4-methylenedioxyphenyl)-6-(prop-1-yloxy)indene-2-carboxylate (1 g, 1.8 mmol) dissolved in a small volume of EtOAc (25 mL) and 10% palladium on activated carbon (93 mg). The resulting solution was stirred under an atmosphere of hydrogen for 120 hours and filtered. The filtrate was concentrated under reduced pressure and the product purified by column chromatography on silica gel (eluant: EtOAc/hexane, 5-10%) to give the title compound as a white foam (0.80 g, 83%). [α]25D= +105.4° (c = 0.13, CH3OH). Anal. Calc. for C30H32O8: C, 69.22; H, 6.20. Found: C, 68.95; H, 6.11.
h) (+)methyl (1S,2S,3S)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. To a solution of methyl (1S,2S,3S)-3-(4-Methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
(0.7 g, 1.3 mmol) in methanol (10 mL) concentrated HCl (0.1 mL) was added and it was
then heated to reflux for 2 h. The solvent was then eliminated under vacuum and the
residue was purified by column chromatography on silica gel (eluant: EtOAc/hexane,
10-20%) to give the title compound as a colorless glass (0.50 g, 78%). [α]25D= +116.0° (c = 0.18, CH3OH). Anal. Calc. for C28H28O7.1/2 H2O: C, 69.27; H, 6.02.
Found: C, 69.59; H, 5.99.
i) (+) Methyl (1S,2S,3S)-3-(2-Carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. A solution of methyl (1S,2S,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.1 g, 0.2 mmol) in dry DMF (2 mL) was added to NaH (6 mg, 0.24 mmol) in a small volume of dry DMF at 0°C. The mixture was stirred at 0°C for 15 min. and ethyl bromoacetate was then added (42 mg, 0.25 mmol). The resulting mixture was stirred at 0°C for 1h. The reaction was then quenched with dilute HCl and extracted with EtOAc. The EtOAc extract was washed with water then brine, dried (MgSO4), filtered and evaporated. The product was purified by column chromatography on silica gel (eluant: EtOAc/hexane, 10-15%) to give the title compound as a glassy solid (82 mg, 68%).[α]25D= +116.0° (c = 0.45, CH3OH). Anal. Calc. for C32 H34O9: C, 68.32; H, 6.09. Found: C, 67.98; H, 6.09.
j) (+) (1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid. To a solution of methyl (1S,2S,3S)-3-(2-carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (20 mg, 0.04 mmol) in dioxane (1 mL) was added 3 M NaOH solution (0.3 mL, 1 mmol). The reaction mixture was heated to reflux for 4 h and after cooling the solvent was eliminated in vacuo dissolved in water and acidified with 3N HCl. The resulting precipitate was collected by filtration and dried to give a white solid (15 mg, 81%); m.p. 99-102°C [α]25D= +38.1° (c = 0.22, CH3OH). Anal. Calc. for C29H28 O9: C, 66.92; H, 5.42. Found C, 67.37; H, 5.32.
EXAMPLE 1A
Preparation of 1-Bromo-4-methoxy-2-methoxymethoxybenzene.
[0049]
a) 1-Bromo-2-hydroxy-4-methoxybenzene. 3-Bromo-2-hydroxy-6-methoxybenzoic acid [T. de Paulis et. al. ,J. Med. Chem., (1985), 28, 1263-1269] (5 g, 0.02 mol) was heated in quinoline (200 mL) at 160°C
for 1 h. On cooling, the product was partitioned between Et2O and 3M HCl. The organic extract was washed with water and brine then dried (MgSO4), filtered and evaporated to give the title compound which was recrystallized from
5% ethyl acetate/hexane (4 g, 97%); m.p. 40-42°C. Anal. Calc. for C7H7 BrO2: C, 41.41; H, 3.48.
Found C, 41.39; H, 3.37.
b) 1-Bromo-4-methoxy-2-methoxymethoxybenzene. To a suspension of NaH (2.5 g, 0.06 mol) in dry DMF (100 mL) at 0°C was added solution
of 1-bromo-2-hydroxy-4-methoxybenzene (10.6 g, 0.05 mol). After stirring at 0°C for
30 min. bromomethyl methyl ether (7.8 g, 0.06 mmol) were dropwise added. The mixture
was warmed to room temperature over 20 min. and then stirred for 2 h, it was then
quenched cautiously by the addition of cold dilute HCl and extracted with EtOAc. The
EtOAc extract was washed successively with; H2O, 5% aqueous NaHCO3, H2O and finally brine. After drying (MgSO4) filtration and evaporation gave liquid. The product was purified by distillation
(85°C, 0.2 mm Hg) to give the title compound as a colorless oil (13.7 g, 97%).
1H NMR (CDCl3) δ 7.40 (d, 1 H, J = 8.9 Hz), 6.75 (d, 1 H, J = 2.8 Hz), 6.46 (dd, 1 H, J = 8.9,
2.8 Hz), 5.23 (s, 2 H), 3.77 (s, 3 H), 3.52 (s, 3 H).
EXAMPLE 2
(1RS,2SR,3RS)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid. dicyclohexylamine salt
[0050] m.p. 182-184°C.
Anal. Calc. for C41H53NO8: C, 71.59; H, 7.77;
N, 2.04. Found: C, 71.67; H, 7.66; N, 2.42.
EXAMPLE 2A
(+) (1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
[0051]
a) (+) Methyl-(1S,2R,3S)-3-[2-(2-t-Butyldimethylsiloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. A solution of methyl-(1S,2S,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (3 g, 6 mmol) in dry DMF (30 mL) was added to NaH (230 mg, 7 mmol, 80%) in a small volume of dry DMF at 0°C. The mixture was stirred at 0°C for 15 min. and 2-t-butyldimethylsiloxyethylbromide was then added dropwise (1.65 g, 8 mmol). The resulting mixture was stirred at 0°C for 3 h. The reaction was then quenched with dilute HCl and extracted with EtOAc. The EtOAc extract was washed with water then brine, dried (MgSO4), filtered and evaporated. The product was purified by column chromatography on silica gel (eluant: EtOAc/hexane, 5-10%) to give the title compound as a colorless oil (520 mg, 18% based on recovery of epimerized starting material).
b) Methyl-(+) (1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate. To a solution of (+) methyl-(1S, 2R, 3S)-3-[2-(2-t-butyldimethylsiloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.520 g, 0.74 mmol) in THF (10 mL) at RT, a 1 M solution of tetra-n-butylammonium fluoride (2.5 mL) in THF was added. The reaction mixture was stirred at RT for 1 h. After concentration in vacuo, the residue was partitioned between ether/ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel (eluant: 20-30% ethyl acetate/hexane) to give the title compound as a colorless foam (0.35 g, 82%).
c) (+) (1S, 2R, 3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid To a solution of methyl-(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.35 g, 0.67 mmol) in methanol/THF 1/2 (15 mL) was added a 0.5 M LiOH solution (5 mL). The reaction mixture was stirred at RT overnight. The solvent was eliminated in vacuo the product dissolved in water and acidified with 3N HCl. The resulting precipitate was collected by filtration and dried to give a white solid (0.31 mg, 91%); m.p. 94-98°C.[α]23D= +73.16° (c = 0.19, CH3OH) Anal. Calc. for C29H29O8Na.11/8 H2O: C, 63.47; H, 5.74. Found: C, 63.39; H, 5.66.
EXAMPLE 3
(1RS,2SR,3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt:
a) Methyl(1RS,2SR,3RS)-3-[2-[(4-Formylpyridin-3-yl)oxyl-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
[0052] To a solution of Methyl (1RS, 2SR, 3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (300 mg, 0.63 mmol) in DMF (4 mL) was added K2CO3 (109 mg, 0.79 mmol) and 3-fluoro-4-formylpyridine (150 mg, 1.2 mmol). The reaction mixture was heated to reflux under argon for 2 h. After cooling to room temperature it was partitioned between 3N HCl and ethyl acetate. The ethyl acetate extract was washed with water, aqueous NaHCO3 and brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, gradient elution from 10% to 20% ethyl acetate/hexanes) to afford the title compound (128 mg, 42%).
b) Methyl (1RS, 2SR, 3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
[0053] To a solution of Methyl (1RS, 2SR, 3RS)-3-[2-[(4-formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (128 mg, 0.24 mmol) in t-BuOH (10 mL) was added a solution of NaClO2 (34 mg, 0.28 mmol) and NH2SO3H (40 mg, 0.42 mmol) in water (6mL). The reaction mixture was stirred at room temperature for 2 h and partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (MgSO4). The solvent was removed in vacuo the residue was purified by flash column chromatography (silica gel, 25% ethyl acetate/hexanes containing 5% of acetic acid) to afford the title compound (90 mg, 69%).
c) (1RS,2SR,3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt
[0054] To a solution of Methyl (1RS, 2SR, 3RS)-3-[2-[(4-Carboxypyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (90, 0.15 mmol) in isopropanol (2 mL) was added 1M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was heated to reflux for 12 h, then concentrated under reduced pressure. The residue was partitioned between dilute HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes containing 5% of acetic acid) to afford the title compound (65 mg, 74%); m.p. 220-222°C (dec.) (disodium salt).
EXAMPLE 4
2,2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
a) 2,2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate
[0055] (1RS,2SR,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid potassium salt (125 mg, 0.54 mmol) (obtained by treatment of the corresponding acid with KHCO3 (54 mg, 0.54 mmol)) was dissolved in DMF (3 ml) and pivaloyloxymethyl iodide (0.54 mmol) (prepared from pivaloyloxymethyl chloride (73 mg, 0.54 mmol) and excess sodium iodide in acetone) added. The reaction mixture was stirred overnight and then partitioned between dil. HCl and ethyl acetate. The organic layer was washed with water and brine then dried (MgSO4 anhyd.) filtered and evaporated. The product was purified by column chromatography to provide the title compound (120 mg, 77%) as a colorless oil.
b) 2,2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-carbobenzyloxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0056] 2,2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (280 mg, 0.5 mmol) in dry DMF (3 ml) was added to NaH (18 mg, 0.6 mmol) in a small volume of dry DMF. The mixture was stirred at RT for 20 min. then benzyl bromoacetate (137 mg, 0.6 mmol) was added. After stirring for 1.5 h the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water then brine, dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound (240 mg, 66%) as a colorless oil.
c) 2.2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
[0057] 2,2-Dimethylpropanoyloxymethyl (1RS,2SR,3RS)-3-(2-carbobenzyloxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (240 mg, 0.3 mmol) was dissolved in a 2:1 mixture of ethyl acetate and ethanol (3 ml) and then 50 mg of 10%Pd/C was added. The mixture was stirred at room temperature under an H2 atmosphere for 3 h. The catalyst was then filtered, the solvent concentrated in vacuo and the resultant oil purified by flash column chromatography. The title compound was obtained (180 mg, 86%) as a colorless oil.
MS (exact mass) (M+Na)+·: 647.2335 (sodium salt)
(D = -2.3. mDa for C33H38O11Na)
mp 190-195°C (dec, sodium salt)
EXAMPLE 5
(1S,2R,3S)-3-[2-[Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy)eth-1-yloxymethoxy]-4-methoxyphenyl-1-(3,4-methlenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylic acid sodium salt
a) Allyl (1S,2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0058] (1S, 2R, 3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (4.8 g, 9.5 mmol) was dissolved in dry acetonitrile (30 ml) and DBU (1.7 ml, 11.4 mmol) was added followed by allyl bromide (3.4 g, 28. mmol). After stirring for 0.5 h. the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound as a pale yellow oil (5.7 g, quantitative).
b) Allyl (1S, 2R, 3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0059] Allyl (1S, 2R, 3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop- -yloxy)indane-2-carboxylate (1.7 g, 3.11 mmol) was dissolved in allyl alcohol (20 ml) and then 15 drops of conc. HCl was added. The resulting solution was stirred at 65°C for 2 h. After removing the solvent the residue was partitioned between water and ethyl acetate. The organic layers were washed with water, 5% aqueous NaHCO3 and brine; then dried (MgSO4 anhyd.), filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound as a pale yellow oil (1.26 g, 81%).
c) Allyl (1S, 2R, 3S)-3-(2-Carbo-1-tert-butoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0060] Allyl (1S, 2R, 3S)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (1.0 g, 2 mmol) in dry DMF (4 ml) was added to NaH (57 mg, 2.4 mmol) in a small volume of dry DMF. The mixture was stirred at RT for 20 min., then tert-butyl bromoacetate (974 mg, 5 mmol) was added. After stirring for 0.5 h., the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water, brine and dried (MgSO4 anhyd.), filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound (1.1 g, 93%) as a pale yellow oil.
d) Allyl (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.
[0061] Allyl (1S, 2R, 3S)-3-(2-carbo-tert-butoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (765 mg, 1.24 mmol) was dissolved in TFA (5 ml) containing a few drops of anisole. The reaction mixture was stirred at RT for 20 min. The solvent was eliminated, the residue was diluted with ethyl acetate, washed with water, brine and dried (MgSO4 anhyd.), filtered and evaporated. The product was purified by column chromatography to provide the title compound (575 mg, 83%) as a colorless oil.
e) Allyl (1S, 2R, 3S)-3-[2-[Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy)eth-1-yloxymethoxy]-4-methoxypheny]-1-(3,4-methlenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylic acid sodium salt
[0062] Allyl (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (287 mg, 0.5 mmol) was dissolved in DMF (5 ml) and Cs2C03 (333 mg, 1 mmol) added followed by (1S)-1-bromoethyl 2-methoxy-2-methylpropionate (225 mg, 1 mmol). The reaction mixture was stirred at RT overnight, then partitioned between water and ethyl acetate, washed with dil. HCl and brine, dried (MgSO4 anhyd.), filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound (260 mg, 74 %) as a colorless oil.
f) (1S,2R,3S)-3-[2-[Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxy)eth-1-yloxymethoxyl-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy)indane-2-carboxylic acid sodium salt
[0063] Allyl (1S,2R,3S)-3-[2-Carbo-(1RS)-1-(2-methoxy-2-methylpropionyloxyeth-1-yloxymethoxy]-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (260 mg, 0.37 mmol) was dissolved in CH2Cl2 (2 ml) and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.037 mmol) added followed by tri-n-butyltin hydride (0.11 ml, 0.4 mol). The reaction mixture was stirred at RT for 3 h then quenched with 3N HCl and stirred for 20 min. The organic layer was diluted with ethyl acetate washed with water then brine, dried (MgSO4 anhyd.), filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound (210 mg, 85 %) as a colorless oil.
MS (exact mass) (M+Na)+·: 687.2415 (sodium salt)
(D = +0.3. mDa for C36H40O12Na)
(1RS,2SR,3RS)-3-[2-[(3-Carboxypyridin-2-yl)oxy]-4-methoxyphenyl]-1(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
(1RS,2SR,3RS)-3-[2-[Carbo(N,N-diethylcarbamoyl)methoxylmethoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
Trans, Trans-1,3-Bis(4-methoxyphenyl)indane-2-carboxamide.
(1RS,2SR,3SR)-3-[4-Methoxy-2-[2-(methylphosphinyl) eth-1-yl]phenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt:
EXAMPLES 6-30
Indan-5-yl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt.
3,5-Dimethoxyphenyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
(1RS)-1-(2-Methoxy-2-methylpropionyloxy)eth-1-yl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
N,N-Dimethylcarbamoylmethyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
Ethoxycarboxymethyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
Benzoyloxymethyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
Cyclohexyloxycarboxymethyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
Ethyl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
(1S,2R,3S)-3-[2-[Carbo-(2',6'-dimethylphenoxy)methoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-(Carbocyclopentyloxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxvphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-[Carbo(indan-5-yloxy)methoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-Carbo(eth-1-yloxy)methoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1RS,2SR,3RS)-3-(2-Carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid
(1RS,2SR,3RS)-2-Trifluoromethylsulfonamidomethyl-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane
Indan-5-yl (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
Cyclopentyl (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt.
Ethoxycarboxymethyl (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt.
(1RS)-1-(1-Methylethoxycarboxy)eth-1-yl (1RS,2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt.
Ethyl (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate sodium salt
(1S,2R,3S)-3-[2-Carbomethoxymethoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-[Carbobenzoyloxymethoxymethoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-(Carboethoxycarboxyloxymethoxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-(Carboacetoxymethoxymethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-(Carbophthalidylmethoxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
(1S,2R,3S)-3-[2-Carbo-(2-methoxy-2-methylpropionyloxymethoxymethoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
EXAMPLE 31
(1S,2R,3S)-3-[2-Carbo-(2,2-dimethylpropanoyloxymethoxymethoxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid sodium salt
[0084] To a solution of (1S,2R,3S)-3-[2-Carboxymethoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid monopotassium salt (170 mg, 0.3 mmol) (obtained by treatment of the corresponding diacid (156 mg, 0.3 mmol) with 1 equiv. of KHCO3 (30 mg, 0.3 mmol)) in DMF (4 mL) pivaloyloxymethyl iodide (74 mg, 0.3 mmol) was added. The reaction mixture was stirred at RT for 0.5 h and more pivaloyloxymethyl iodide was then added (20 mg. 0.08 mmol) and then stirred for an additional 0.5 h. The reaction mixture was partitioned between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, Ethyl Acetate/hexane/HOAc 30/65/5) to obtain the desired compound as a white foam (140 mg, 73 %) as the free acid which was converted to its sodium salt. m.p. 128 - 133°C.
MS (exact mass) M++Na : 679.2116 (sodium salt)
(D = +1.2 mDa for C35H37O11Na2)
EXAMPLE 32
[0085] Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Inhalant Formulation
[0086] A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
| Tablets/Ingredients | Per Tablet |
| 1. Active ingredient (Cpd of Form. I) |
40 mg |
| 2. Corn Starch | 20 mg |
| 3. Alginic acid | 20 mg |
| 4. Sodium Alginate | 20 mg |
| 5. Mg stearate | 1.3 mg |
| 2.3 mg |
Procedure for tablets:
[0087]
- Step 1
- Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
- Step 2
- Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
- Step 3
- The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
- Step 4
- The wet granules are then dried in an oven at 140°F (60°C) until dry.
- Step 5
- The dry granules are lubricated with ingredient No. 5.
- Step 6
- The lubricated granules are compressed on a suitable tablet press.
Parenteral Formulation
[0088] A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then steriled by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
wherein:
R1 is -X(CH2)nAr or -X(CH2)nR8 or
R2 is hydrogen, Ar, C1-4alkyl or (c);
P1 is -X(CH2)nR8;
P2 is -X(CH2)nR8 or -X-R9-Y;
R3 and R5 are independently hydrogen, R11, OH, C1-8alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, R11CO2R7, -X-R9-Y or -X(CH2)nR8, wherein each methylene group within -X(CH2)nR8 may be unsubstituted or substituted by one or two -(CH2)nAr groups;
R4 is hydrogen, R11, OH, C1-5alkoxy, S(O)qR11, N(R6)2, -X(R11), Br, F, I, Cl or NHCOR6, wherein the C1-5alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
R6 is independently hydrogen or C1-4alkyl;
R7 is independently hydrogen, C1-10alkyl, C2-10alkenyl or C2-8 alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, CO2R12, halogen or XC1-5alkyl; or R7 is (CH2)nAr;
R8 is hydrogen, R11, CO2R7, CO2C(R11)2O(CO)XR7, PO3(R7)2, SO2NR7R11, NR7SO2R11, CONR7SO2R11, SO3R7, SO2R7, P(O)(OR7)R7, CN, C(O)N(R6)2, -CO2(CH2)mC(O)N(R6)2, C(R11)2N(R7)2, tetrazole or OR6;
R9 is (CH2)n, divalent C1-10alkyl, divalent C2-10alkenyl or phenyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, COOH, halogen, or R9 may be 〉C=O or XC1-5alkyl;
R10 is R3 or R4;
R11 is hydrogen, Ar, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen; with the proviso that when R11 is present in the group R11CO2R7, R11 is not hydrogen.
R12 is hydrogen, C1-6alkyl, C2-6alkenyl or C2-7alkynyl;
X is (CH2)n, O, NR6 or S(O)q;
Y is CH3 or X(CH2)nAr;
Ar is:
naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more R3 or R4 groups;
A is C=O or [C(R6)2]m;
B is -CH2- or -O-;
Z1 and Z2 are independently hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, OH, C1-8alkoxy, S(O)qC1-8alkyl, N(R6)2, Br, F, I, Cl, NHCOR6, -X-R9-Y, -X(CH2)nR8, phenyl, benzyl or C3-6cycloalkyl wherein the C1-8alkyl, C2-8alkenyl or C2-8alkynyl may be optionally substituted by COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2, or halogen; or Z1 and Z2 together may be -O-A-O- on contiguous carbons;
Z3 is Z1 or -X-R9-Y;
q is zero, one or two;
n is an integer from 0 to six;
m is 1, 2 or 3; and the dotted line indicates the optional presence of a double bond; or a pharmaceutically acceptable salt thereof; provided that
• R2 is not hydrogen when X is S(O)q;
• R11 and R7 are not hydrogen when q is 1 or 2 in S(O)qR11 or S(O)qR7;
• when the optional double bond is present there is only one R10 and there is no P1 and P2 is not NR6R9Y;
• when the optional double bond is present in Formula (I) and X-R2 is attached to the double bond, X is not NR6;
• when the optional double bond is present and R1 is attached directly to the double bond, R1 is not NR6Ar;
• when R3, R5, Z1, Z2, or Z3 is X(CH2)nR8 and n is not 0, X is oxygen or NR6 when R8 is OR6 or CO2H;
• when R8 is CO2C(R11)2O(CO)XR7, X is not S(O)q;
• the compound of Formula I is not methyl 1,3-diphenylindene-2-carboxylate; ethyl 1,3-diphenylindene-2-carboxylate; 1,3-diphenyl-2-cyanoindene; or ethyl 1,3-diphenyl-3-hydroxyindane-2-carboxylate; and further provided that compounds wherein:
R1 is -X(CH2)nAr or -X(CH2)nR8 or
R2 is hydrogen, Ar or (c);
P1 is -X(CH2)nR8;
P2 is -X(CH2)nR8, or -XR9Y;
R3 and R5 are independently hydrogen, R11, OH, C1-8alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, -XR9- Y or -X(CH2)nR8 wherein the methylene groups of -X(CH2)nR8 may be unsubstituted or substituted by one or more -(CH2)nAr groups;
R4 is hydrogen, R11, OH, C1-5alkoxy, S(O)qR11, N(R6)2, -X(R11), Br, F, I, Cl or NHCOR6 wherein the C1-5alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
R6 is independently hydrogen or C1-4alkyl;
R7 is independently hydrogen, C1-6alkyl or (CH2)nAr;
R8 is hydrogen, R11, CO2H, PO3H2, P(O)(OH)R7 or tetrazole;
R9 is C1-10alkyl, C2-10alkenyl or phenyl all of which may be unsubstituted or substituted by one or more OH, N(R6)2, COOH, halogen or XC1-5alkyl;
R10 is R3 or R4;
R11 is C1-8alkyl, C2-8alkenyl, C2-8alkynyl all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2 or halogen;
X is (CH2)n, O, NR6 or S(O)q;
Y is CH3 or -CH2X(CH2)nAr;
Ar is:
naphthyl, indolyl, pyridyl or thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more R3 or R4 groups;
A is C=O, or [C(R6)2]m;
B is -CH2- or -O-;
Z1 and Z2 are independently hydrogen; C1-8alkyl, C2-8alkenyl, C2-8alkynyl, OH, C1-8alkoxy, S(O)qC1-8alkyl, N(R6)2, Br, F, I, Cl, NHCOR6, -X(CH2)nR8, phenyl, benzyl or C3-6cycloalkyl wherein the C1-8alkyl, C2-8alkenyl or C2-8alkynyl may be optionally substituted by COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2 or halogen; or Z1 and Z2 together may be -O-A-O- on contiguous carbons;
Z3 is Z1 or XR9Y;
q is zero, one or two;
n is an integer from 0 to six; and
m is 1, 2 or 3; are excluded.
R1 is X(CH2)nAr, dihydrobenzofuranyl, benzodioxanyl, cyclohexyl or C1- 4alkyl;
R2 is a moiety of formula (a) or (b), C1-4alkyl, indolyl or hydrogen;
R3 and R5 are independently hydrogen, OH, C1-5alkoxy, halogen, -OC1- 4alkyl phenyl, R11CO2R7, C1-4alkyl, N(R6)2, NH(CO)CH3, -X(CH2)nR8, -X-R9-Y, pyridyl, phenyl or S(O)qC1-5alkyl;
R4 is hydrogen, OH, C1-5alkoxy, halogen, C1-4alkyl, N(R6)2, NH(CO)CH3 or S(O)qC1-5alkyl;
Z1, Z2 and Z3 are independently X-R9-Y, benzyl, hydrogen, OH, C1- 5alkoxy, -N(R6)2, S(O)qC1-8alkyl, NHCOR6, X(CH2)nR8 or halogen, or Z1 and Z2 together may be -O-A-O- on contiguous carbons;
P1 and P2 are independently hydrogen, CO2H or tetrazole;
Ar is a moiety of formula (a), or (b) or pyridyl; and
X is (CH2)n or oxygen.
R3 is hydrogen, -X(CH2)nR8 or R11CO2R7;
R4 and R5 are independently hydrogen, OH, C1-5alkoxy, SC1-5alkyl, F, Br, C1-3alkyl or NH2; and
Z1 and Z3 are hydrogen and Z2 is hydrogen, OH, C1-5alkoxy, halogen, X(CH2)nR8, NH2, benzyl or NH(CO)CH3, or Z1 and Z2 together may be -O-A-O-on contiguous carbons.
R1 is a moiety of formula (b);
A is CH2, B is -O-;
there is no optional double bond;
R1 and XR2 are trans to P1;
Z2 is OH, C1-5alkoxy, -OCH2CH2CH3 or hydrogen;
Z1 is hydrogen;
R3 is hydrogen, XAr, X(CH2)qCO2H, X(CH2)qCONR7SO2R11, or CH=CHCO2H;
R4 is hydrogen or C1-2alkoxy; and
R5, R10 and P2 are hydrogen.
wherein Z1, Z2, Z3 and R1 are as defined in claim 1 or groups convertable thereto, and X is C1-5alkyl, with an organomagnesium compound of formula (12):
R2-(CH2)n-MgBr (12)
wherein R2 is as defined in claim 1 or a group convertable thereto, in a suitable solvent to provide a compound of formula (13):
which is reduced and thereafter, when desired or necessary undergoes:
a) insertion of R10 (when other than hydrogen) through conjugate additon; and/or
b) alkylation or acylation to give compounds wherein P1 and P2 are other than CO2H; and/or
c) conversion of groups R1, R2, Z1, Z2 and Z3 to other groups R1, R2, Z1, Z2 and Z3;
to afford a compound of formula (I).in der:
R1 einen Rest der Formel -X(CH2)nAr oder -X(CH2)nR8 oder
bedeutet;
R2 ein Wasserstoffatom, einen Ar-, C1-4-Alkylrest oder (c) darstellt;
P1 einen Rest der Formel -X(CH2)nR8 bedeutet;
P2 einen Rest der Formel -X(CH2)nR8 oder -X-R9-Y darstellt;
R3 und R5 unabhängig voneinander ein Wasserstoffatom, den Rest R11, eine OH-Gruppe, einen C1-8-Alkoxyrest, einen Rest der Formel S(O)qR11, N(R6)2, ein Brom-, Fluor-, Iod-, Chloratom, eine CF3-Gruppe, einen Rest der Formel NHCOR6, R11CO2R7, -X-R9-Y oder -X(CH2)nR8 bedeuten, wobei jede Methylengruppe in dem Rest der Formel -X(CH2)nR8 unsubstituiert oder mit einem oder zwei Resten der Formel -(CH2)nAr substituiert sein kann;
R4 ein Wasserstoffatom, den Rest R11, eine OH-Gruppe, einen C1-5-Alkoxyrest, einen Rest der Formel S(O)qR11, N(R6)2, -X(R11), ein Brom-, Fluor-, Iod-, Chloratom oder einen Rest der Formel NHCOR6 darstellt, wobei der C1-5-Alkoxyrest unsubstituiert oder mit einer OH-, Methoxygruppe oder einem Halogenatom substituiert sein kann;
R6 unabhängig ein Wasserstoffatom oder einen C1-4-Alkylrest bedeutet;
R7 unabhängig ein Wasserstoffatom, einen C1-10-Alkyl-, C2-10-Alkenyl- oder C2-8-Alkinylrest darstellt, die alle unsubstituiert oder mit einer oder mehreren OH-Gruppen, Resten der Formel N(R6)2, CO2R12, Halogenatomen oder XC1-5-Alkylresten substituiert sein können; oder R7 einen Rest der Formel (CH2)nAr bedeutet;
R8 ein Wasserstoffatom, den Rest R11, einen Rest der Formel CO2R7, CO2C(R11)2O-(CO)XR7, PO3(R7)2, SO2NR7R11, NR7SO2R11, CONR7SO2R11, SO3R7, SO2R7, P(O)(OR7)R7, eine CN-Gruppe, einen Rest der Formel C(O)N(R6)2, -CO2(CH2)mC(O)N(R6)2, C(R11)2N(R7)2, eine Tetrazolgruppe oder einen Rest der Formel OR6 darstellt;
R9 einen Rest der Formel (CH2)n, einen zweiwertigen C1-10-Alkyl-, zweiwertigen C2-10-Alkenylrest oder eine Phenylgruppe bedeutet, die alle unsubstituiert oder mit einer oder mehreren OH-Gruppen, Resten der Formel N(R6)2, COOH-Gruppen, Halogenatomen substituiert sein können; oder R9 eine >C=0-Gruppe oder einen XC1-5-Alkylrest darstellen kann;
R10 den Rest R3 oder R4 bedeutet;
R11 ein Wasserstoffatom, einen Ar-, C1-8-Alkyl-, C2-8-Alkenyl- oder C2-8-Alkinylrest darstellt, die alle unsubstituiert oder mit einer oder mehreren OH-, CH2OH-Gruppen, Resten der Formel N(R6)2 oder Halogenatomen substituiert sein können; mit der Maßgabe, dass, wenn R11 in dem Rest der Formel R11CO2R7 vorliegt, R11 kein Wasserstoffatom bedeutet;
R12 ein Wasserstoffatom, einen C1-6-Alkyl-, C2-6-Alkenyl- oder C2-7-Alkinylrest darstellt;
X einen Rest der Formel (CH2)n, ein Sauerstoffatom, einen Rest der Formel NR6 oder S(O)q bedeutet;
Y eine CH3-Gruppe oder einen Rest der Formel X(CH2)nAr darstellt;
Ar einen Rest der Formel:
eine Naphthyl-, Indolyl-, Pyridyl-, Thienyl-, Oxazolidinyl-, Oxazolyl-, Thiazolyl-, Isothiazolyl-, Pyrazolyl-, Triazolyl-, Tetrazolyl-, Imidazolyl-, Imidazolidinyl-, Thiazolidinyl-, Isoxazolyl-, Oxadiazolyl-, Thiadiazolyl-, Morpholinyl-, Piperidinyl-, Piperazinyl-, Pyrrolyl- oder Pyrimidylgruppe bedeutet, die alle unsubstituiert oder mit einem oder mehreren Resten R3 oder R4 substituiert sein können;
A eine C=O-Gruppe oder einen Rest der Formel [C(R6)2]m darstellt;
B eine -CH2- oder -O-Gruppe bedeutet;
Z1 und Z2 unabhängig voneinander ein Wasserstoffatom, einen C1-8-Alkyl-, C2-8-Alkenyl-, C2-8-Alkinylrest, eine OH-Gruppe, einen C1-8-Alkoxy-, S(O)qC1-8-Alkylrest, einen Rest der Formel N(R6)2, ein Brom-, Fluor-, Iod-, Chloratom, einen Rest der Formel NHCOR6, -X-R9-Y, -X(CH2)nR8, eine Phenyl-, Benzylgruppe oder einen C3-6-Cycloalkylrest darstellen, wobei der C1-8-Alkyl-, C2-8-Alkenyl- oder C2-8-Alkinylrest gegebenenfalls mit einer COOH-, OH-Gruppe, einem Rest der Formel CO(CH2)nCH3, CO(CH2)nCH2N(R6)2 oder einem Halogenatom substituiert sein kann; oder Z1 und Z2 zusammen einen Rest der Formel-O-A-O- an benachbarten Kohlenstoffatomen bedeuten können;
Z3 den Rest Z1 oder einen Rest der Formel -X-R9-Y darstellt;
q null, eins oder zwei ist;
n eine ganze Zahl von 0 bis sechs ist;
m 1, 2 oder 3 ist; und die punktierte Linie die mögliche Anwesenheit einer Doppelbindung anzeigt; oder ein pharmazeutisch verträgliches Salz davon; mit der Maßgabe, dass
• R2 kein Wasserstoffatom bedeutet, wenn X einen Rest der Formel S(O)q darstellt;
• R11 und R7 kein Wasserstoffatom bedeuten, wenn q in dem Rest der Formel S(O)qR11 oder S(O)qR7 1 oder 2 ist;
• wenn die gegebenenfalls vorhandene Doppelbindung vorliegt, es nur einen Rest R10 und keinen Rest P1 gibt, und P2 keinen Rest der Formel NR6R9Y darstellt;
• wenn die gegebenenfalls vorhandene Doppelbindung in Formel (I) vorliegt, und der Rest der Formel X-R2 an die Doppelbindung gebunden ist, X keinen Rest der Formel NR6 bedeutet;
• wenn die gegebenenfalls vorhandene Doppelbindung vorliegt, und der Rest R1 direkt an die Doppelbindung gebunden ist, R1 keinen Rest der Formel NR6Ar darstellt;
• wenn der Rest R3, R5, Z1, Z2 oder Z3 einen Rest der Formel X(CH2)nR8 bedeutet, und n nicht 0 ist, X ein Sauerstoffatom oder einen Rest der Formel NR6 darstellt, wenn R8 einen Rest der Formel OR6 oder eine CO2H-Gruppe bedeutet;
• wenn R8 einen Rest der Formel CO2C(R11)2O(CO)XR7 darstellt, X keinen Rest der Formel S(O)q bedeutet;
• die Verbindung der Formel (I) kein 1,3-Diphenylinden-2-carbonsäuremethylester, 1,3-Diphenylinden-2-carbonsäureethylester, 1,3-Diphenyl-2-cyanoinden oder 1,3-Diphenyl-3-hydroxyindan-2-carbonsäureethylester ist;
und ferner mit der Maßgabe, dass Verbindungen, in denen:R1 einen Rest der Formel -X(CH2)nAr oder -X(CH2)nR8 oder
darstellt;
R2 ein Wasserstoffatom, einen Ar-Rest oder (c) bedeutet;
P1 einen Rest der Formel -X(CH2)nR8 darstellt;
P2 einen Rest der Formel -X(CH2)nR8 oder -XR9-Y bedeutet;
R3 und R5 unabhängig voneinander ein Wasserstoffatom, den Rest R11, eine OH-Gruppe, einen C1-8-Alkoxyrest, einen Rest der Formel S(O)qR11, N(R6)2, ein Brom-, Fluor-, Iod-, Chloratom, eine CF3-Gruppe, einen Rest der Formel NHCOR6, -XR9-Y oder -X(CH2)n-R8 darstellen, wobei die Methylengruppen des Restes der Formel -X(CH2)nR8 unsubstituiert oder mit einem oder mehreren Resten der Formel -(CH2)nAr substituiert sein können;
R4 ein Wasserstoffatom, den Rest R11, eine OH-Gruppe, einen C1-5-Alkoxyrest, einen Rest der Formel S(O)qR11, N(R6)2, -X(R11), ein Brom-, Fluor-, Iod-, Chloratom oder einen Rest der Formel NHCOR6 bedeutet, wobei der C1-5-Alkoxyrest unsubstituiert oder mit einer OH-, Methoxygruppe oder einem Halogenatom substituiert sein kann;
R6 unabhängig ein Wasserstoffatom oder einen C1-4-Alkylrest darstellt;
R7 unabhängig ein Wasserstoffatom, einen C1-6-Alkylrest oder einen Rest der Formel (CH2)nAr bedeutet;
R8 ein Wasserstoffatom, den Rest R11, eine CO2H-, PO3H2-Gruppe, einen Rest der Formel P(O)(OH)R7 oder eine Tetrazolgruppe darstellt;
R9 einen C1-10-Alkyl-, C2-10-Alkenylrest oder eine Phenylgruppe bedeutet, die alle unsubstituiert oder mit einer oder mehreren OH-Gruppen, Resten der Formel N(R6)2, COOH-Gruppen, Halogenatomen oder XC1-5-Alkylresten substituiert sein können;
R10 den Rest R3 oder R4 darstellt;
R11 einen C1-8-Alkyl-, C2-8-Alkenyl- oder C2-8-Alkinylrest bedeutet, die alle unsubstituiert oder mit einer oder mehreren OH-, CH2OH-Gruppen, Resten der Formel N(R6)2 oder Halogenatomen substituiert sein können;
X einen Rest der Formel (CH2)n, ein Sauerstoffatom, einen Rest der Formel NR6 oder S(O)q darstellt;
Y eine CH3-Gruppe oder einen Rest der Formel -CH2X(CH2)nAr bedeutet;
Ar einen Rest der Formel:
eine Naphthyl-, Indolyl-, Pyridyl- oder Thienyl-, Oxazolidinyl-, Oxazolyl-, Thiazolyl-, Isothiazolyl-, Pyrazolyl-, Triazolyl-, Tetrazolyl-, Imidazolyl-, Imidazolidinyl-, Thiazolidinyl-, Isoxazolyl-, Oxadiazolyl-, Thiadiazolyl-, Morpholinyl-, Piperidinyl-, Piperazinyl-, Pyrrolyl- oder Pyrimidylgruppe darstellt, die alle unsubstituiert oder mit einem oder mehreren Resten R3 oder R4 substituiert sein können;
A eine C=O-Gruppe oder einen Rest der Formel [C(R6)2]m bedeutet;
B eine -CH2- oder -O-Gruppe darstellt;
Z1 und Z2 unabhängig voneinander ein Wasserstoffatom, einen C1-8-Alkyl-, C2-8-Alkenyl-, C2-8-Alkinylrest, eine OH-Gruppe, einen C1-8-Alkoxy-, S(O)qC1-8-Alkylrest, einen Rest der Formel N(R6)2, ein Brom-, Fluor-, Iod-, Chloratom, einen Rest der Formel NHCOR6, -X(CH2)nR8, eine Phenyl-, Benzylgruppe oder einen C3-6-Cycloalkylrest bedeuten, wobei der C1-8-Alkyl-, C2-8-Alkenyl- oder C2-8-Alkinylrest gegebenenfalls mit einer COOH-, OH-Gruppe, einem Rest der Formel CO(CH2)nCH3, CO(CH2)nCH2N(R6)2 oder einem Halogenatom substituiert sein kann; oder Z1 und Z2 zusammen einen Rest der Formel -O-A-O- an benachbarten Kohlenstoffatomen darstellen können;
Z3 den Rest Z1 oder einen Rest der Formel XR9Y bedeutet;
q null, eins oder zwei ist;
n eine ganze Zahl von 0 bis sechs ist; und
m 1, 2 oder 3 ist;
ausgeschlossen sind.R1 einen Rest der Formel X(CH2)nAr, eine Dihydrobenzofuranyl-, Benzodioxanyl-, Cyclohexylgruppe oder einen C1-4-Alkylrest darstellt;
R2 eine Einheit der Formel (a) oder (b), einen C1-4-Alkylrest, eine Indolylgruppe oder ein Wasserstoffatom bedeutet;
R3 und R5 unabhängig voneinander ein Wasserstoffatom, eine OH-Gruppe, einen C1-5-Alkoxyrest, ein Halogenatom, einen -OC1-4-Alkylphenylrest, einen Rest der Formel R11CO2R7, einen C1-4-Alkylrest, einen Rest der Formel N(R6)2, NH(CO)CH3, -X-(CH2)nR8, -X-R9-Y, eine Pyridyl-, Phenylgruppe oder einen S(O)qC1-5-Alkylrest darstellen;
R4 ein Wasserstoffatom, eine OH-Gruppe, einen C1-5-Alkoxyrest, ein Halogenatom, einen C1-4-Alkylrest, einen Rest der Formel N(R6)2, NH(CO)CH3 oder einen S(O)qC1-5-Alkylrest bedeutet;
Z1, Z2 und Z3 unabhängig voneinander einen Rest der Formel X-R9-Y, eine Benzylgruppe, ein Wasserstoffatom, eine OH-Gruppe, einen C1-5-Alkoxyrest, einen Rest der Formel -N(R6)2, einen S(O)qC1-8-Alkylrest, einen Rest der Formel NHCOR6, X(CH2)nR8 oder ein Halogenatom darstellen; oder Z1 und Z2 zusammen einen Rest der Formel -O-A-O- an benachbarten Kohlenstoffatomen bedeuten können;
P1 und P2 unabhängig voneinander ein Wasserstoffatom, eine CO2H- oder Tetrazolgruppe darstellen;
Ar eine Einheit der Formel (a) oder (b) oder eine Pyridylgruppe bedeutet; und
X einen Rest der Formel (CH2)n oder ein Sauerstoffatom darstellt.
R3 ein Wasserstoffatom, einen Rest der Formel -X(CH2)nR8 oder R11CO2R7 bedeutet;
R4 und R5 unabhängig voneinander ein Wasserstoffatom, eine OH-Gruppe, einen C1-5-Alkoxy-, SC1-5-Alkylrest, ein Fluor-, Bromatom, einen C1-3-Alkylrest oder eine NH2-Gruppe darstellen; und
Z1 und Z3 ein Wasserstoffatom bedeuten, und Z2 ein Wasserstoffatom, eine OH-Gruppe, einen C1-5-Alkoxyrest, ein Halogenatom, einen Rest der Formel X(CH2)nR8, eine NH2-, Benzyl- oder NH(CO)CH3-Gruppe bedeuten, oder Z1 und Z2 zusammen einen Rest der Formel -O-A-O- an benachbarten Kohlenstoffatomen bedeuten können.
R1 eine Einheit der Formel (b) darstellt;
A eine CH2-Gruppe bedeutet, und B eine -O-Gruppe darstellt;
es keine gegebenenfalls vorhandene Doppelbindung gibt;
R1 und XR2 in trans-Stellung zu P1 stehen;
Z2 eine OH-Gruppe, einen C1-5-Alkoxyrest, eine -OCH2CH2CH3-Gruppe oder ein Wasserstoffatom bedeutet;
Z1 ein Wasserstoffatom darstellt;
R3 ein Wasserstoffatom, einen Rest der Formel XAr, X(CH2)qCO2H, X(CH2)qCON-R7SO2R11 oder eine CH=CHCO2H-Gruppe bedeutet;
R4 ein Wasserstoffatom oder einen C1-2-Alkoxyrest darstellt; und
R5, R10 und P2 ein Wasserstoffatom bedeuten.
in der Z1, Z2, Z3 und R1 wie in Anspruch 1 definiert sind oder dazu umwandelbare Reste darstellen, und X einen C1-5-Alkylrest bedeutet, mit einer Organomagnesiumverbindung der Formel (12):
R2-(CH2)n-MgBr (12),
in der R2 wie in Anspruch 1 definiert ist oder einen dazu umwandelbaren Rest darstellt, in einem geeigneten Lösungsmittel umfasst, wobei eine Verbindung der Formel (13):
bereitgestellt wird, die reduziert wird und danach, falls erwünscht oder notwendig:
a) eine Einführung des Restes R10 (wenn er kein Wasserstoffatom bedeutet) durch konjugierte Addition und/oder
b) eine Alkylierung oder Acylierung, wobei sich Verbindungen ergeben, in denen P1 und P2 keine CO2H-Gruppe darstellen, und/oder
c) eine Umwandlung der Reste R1, R2, Z1, Z2 und Z3 in andere Reste R1, R2, Z1, Z2 und Z3 durchläuft, wobei sich eine Verbindung der Formel (I) ergibt.
dans laquelle :
R1 représente un groupe -X(CH2)nAr ou -X(CH2)nR8 ou
R2 représente l'hydrogène, un groupe Ar, alkyle en C1 à C4 ou (c) ;
P1 représente un groupe -X(CH2)nR8 ;
P2 représente un groupe -X(CH2)nR8 ou -X-R9-Y ;
R3 et R5 représentent, indépendamment, l'hydrogène, un groupe R11, OH, alkoxy en C1 à C8, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, R11CO2R7, -X-R9-Y ou -X(CH2)nR8, chaque groupe méthylène dans -X(CH2)nR8 pouvant être non substitué ou substitué avec un ou deux groupes -(CH2)nAr ;
R4 représente l'hydrogène, un groupe R11, OH, alkoxy en C1 à C5, S(O)qR11, N(R6)2, -X(R11), Br, F, I, Cl ou NCOR6, le groupe alkoxy en C1 à C5 pouvant être non substitué ou substitué avec un groupe OH, méthoxy ou halogéno ;
R6 réprésente, indépendamment, l'hydrogène ou un groupe alkyle en C1 à C4 ;
R7 représente, indépendamment, l'hydrogène, un groupe alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C2 à C8, tous ces groupes pouvant être non substitués ou substitués avec un ou plusieurs groupes OH, N(R6)2, CO2R12, halogéno ou X(alkyle en C1 à C5) ; ou bien R7 représente un groupe (CH2)nAr ;
R8 représente l'hydrogène, un groupe R11, CO2R7, CO2C(R11)2O(CO)XR7, PO3(R7)2, SO2NR7R11, NR7SO2R11, CONR7SO2R11, SO3R7, SO2R7, P(O)(OR7)R7, CN, C(O)N(R6)2, -CO2(CH2)mC(O)N(R6)2, C(R11)2N(R7)2, tétrazole ou OR6 ;
R9 représente un groupe (CH2)n, alkyle en C1 à C10 divalent, alcényle en C2 à C10 divalent ou phényle, tous ces groupes pouvant être non substitués ou substitués avec un ou plusieurs groupes OH, N(R6)2, COOH, halogéno, ou bien R9 peut représenter un groupe 〉C=O ou X(alkyle en C1 à C5) ;
R10 représente R3 ou R4 ;
R11 représente l'hydrogène, un groupe Ar, alkyle en C1 à C8, alcényle en C2 à C8 ou alcynyle en C2 à C8, tous ces groupes pouvant être non substitués ou substitués avec un ou plusieurs groupes OH, CH2OH, N(R6)2 ou halogéno ; sous réserve que, lorsque R11 est présent dans le groupe R11CO2R7, R11 ne représente pas l'hydrogène ;
R12 représente l'hydrogène, un groupe alkyle en C1 à C6, alcényle en C2 à C6 ou alcynyle en C2 à C7 ;
X représente un groupe (CH2)n, O, NR6 ou S(O)q ;
Y représente un groupe CH3 ou X(CH2)nAr ;
Ar représente un groupe :
naphtyle, indolyle, pyridyle, thiényle, oxazolidinyle, oxazolyle, thiazolyle, isothiazolyle, pyrazolyle, triazolyle, tétrazolyle, imidazolyle, imidazolidinyle, thiazolidinyle, isoxazolyle, oxadiazolyle, thiadiazolyle, morpholinyle, pipéridinyle, pipérazinyle, pyrrolyle ou pyrimidiyle ; tous ces groupes pouvant être non substitués ou substitués avec un ou plusieurs groupes R3 ou R4 ;
A représente un groupe C=O ou [C(R6)2]m ;
B représente un groupe -CH2- ou -O- ;
Z1 et Z2 représentent, indépendamment, l'hydrogène, un groupe alkyle en C1 à C8, alcényle en C2 à C8, alcynyle en C2 à C8, OH, alkoxy en C1 à C8, S(O)q(alkyle en C1 à C8), N(R6)2, Br, F, I, Cl, NHCOR6, -X-R9-Y, -X(CH2)nR8, phényle, benzyle ou cycloalkyle en C3 à C6, ledit groupe alkyle en C1 à C8, alcényle en C2 à C8 ou alcynyle en C2 à C8 pouvant être facultativement substitué avec un groupe COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2 ou halogéno ; ou bien Z1 et Z2, conjointement, peuvent représenter un groupe -O-A-O- sur des atomes de carbone contigus ;
Z3 représente un groupe Z1 ou -X-R9-Y ;
q est égal à zéro, un ou deux ;
n représente un nombre entier de 0 à six ;
m est égal à 1, 2 ou 3 ; et la ligne discontinue indique la présence facultative d'une double liaison ; ou un de ses sels pharmaceutiquement acceptables ; sous réserve que
. R2 ne représente pas l'hydrogène lorsque X représente un groupe S(O)q ;
. R11 et R7 ne représentent pas l'hydrogène lorsque q est égal à 1 ou 2 dans S(O)qR11 ou S(O)qR7 ;
. lorsque la double liaison facultative est présente, il existe un seul groupe R10 et il n'existe aucun groupe P1 et P2 ne représente pas un groupe NR6R9Y ;
. lorsque la double liaison facultative est présente dans la formule (I) et X-R2 est fixé à la double liaison, X'ne représente pas un groupe NR6 ;
. lorsque la double liaison facultative est présente et R1 est fixé directement à la double liaison, R1 ne représente pas un groupe NR6Ar ;
. lorsque R3, R5, Z1, Z2 ou Z3 représente un groupe X(CH2)nR8 et n n'est pas égal à 0, X représente l'oxygène ou un groupe NR6 lorsque R8 représente un groupe OR6 ou CO2H ;
. lorsque R8 représente un groupe CO2C(R11)2O(CO)XR7, X ne représente pas un groupe S(O)q ;
. le composé de formule I ne consiste pas en le 1,3-diphénylindène-2-carboxylate de méthyle ; le 1,3-diphénylindène-2-carboxylate d'éthyle ; le 1,3-diphényl-2-cyano-indène ou le 1,3-diphényl-3-hydroxyindane-2-carboxylate d'éthyle ;
et sous réserve en outre que les composés dans lesquels :R1 représente un groupe -X(CH2)nAr ou -X(CH2)nR8 ou
R2 représente l'hydrogène, un groupe Ar ou (c) ;
P1 représente un groupe -X(CH2)R8 ;
P2 représente un groupe -X(CH2)nR8 ou -XR9-Y ;
R3 et R5 représentent, indépendamment, l'hydrogène, un groupe R11, OH, alkoxy en C1 à C8, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, -XR9-Y ou -X(CH2)nR8, les groupes méthylène de -X(CH2)nR8 pouvant être non substitués ou substitués avec un ou plusieurs groupes -(CH2)nAr ;
R4 représente l'hydrogène, un groupe R11, OH, alkoxy en C1 à C5, S(O)qR11, N(R6)2, -X(R11), Br, F, I, Cl ou NCOR6, le groupe alkoxy en C1 à C5 pouvant être non substitué ou substitué avec un groupe OH, méthoxy ou halogéno ;
R6 représente, indépendamment, l'hydrogène ou un groupe alkyle en C1 à C4 ;
R7 représente, indépendamment, l'hydrogène, un groupe alkyle en C1 à C6 ou (CH2)nAr ;
R8 représente l'hydrogène, un groupe R11, CO2H, PO3H2, P(O) (OH)R7 ou tétrazole ;
R9 représente un groupe alkyle en C1 à C10, alcényle en C2 à C10 ou phényle, tous ces groupes pouvant être non substitués ou substitués avec un ou plusieurs groupes OH, N(R6)2, COOH, halogéno ou X(alkyle en C1 à C5) ;
R10 représente un groupe R3 ou R4 ;
R11 représente un groupe alkyle en C1 à C8, alcényle en C2 à C8 ou alcynyle en C2 à C8, tous ces groupes pouvant être non substitués ou substitués avec un ou plusieurs groupes OH, CH2OH, N(R6)2 ou halogéno ;
X représente un groupe (CH2)n, O, NR6 ou S(O)q ;
Y représente un groupe CH3 ou CH2X(CH2)nAr ;
Ar représente un groupe :
naphtyle, indolyle, pyridyle ou thiényle, oxazolidinyle, oxazolyle, thiazolyle, isothiazolyle, pyrazolyle, triazolyle, tétrazolyle, imidazolyle, imidazolidinyle, thiazolidinyle, isoxazolyle, oxadiazolyle, thiadiazolyle, morpholinyle, pipéridinyle, pipérazinyle, pyrrolyle ou pyrimidyle ; tous ces groupes pouvant être non substitués ou substitués avec un ou plusieurs groupes R3 ou R4 ;
A représente un groupe C=O ou [C(R6)2]m ;
B représente un groupe -CH2- ou -O- ;
Z1 et Z2 représentent, indépendamment, l'hydrogène, un groupe alkyle en C1 à C8, alcényle en C2 à C8, alcynyle en C2 à C8, OH, alkoxy en C1 à C8, S(O)q(alkyle en C1 à C8), N(R6)2, Br, F, I, Cl, NHCOR6, -X(CH2)nR8, phényle, benzyle ou cycloalkyle en C3 à C6, ledit groupe alkyle en C1 à C8, alcényle en C2 à C8 ou alcynyle en C2 à C8 pouvant être facultativement substitué avec un groupe COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2 ou halogéno ; ou bien Z1 et Z2, conjointement, peuvent représenter un groupe -O-A-O- sur des atomes de carbone contigus ;
Z3 représente un groupe Z1 ou XR9-Y ;
q est égal à zéro, un ou deux ;
n représente un nombre entier de 0 à six ; et
m est égal à 1, 2 ou 3 ; soient exclus.
R1 représente un groupe X(CH2)nAr, dihydrobenzofurannyle, benzodioxannyle, cyclohexyle ou alkyle en C1 à C4 ;
R2 représente un groupement de formule (a) ou (b), alkyle en C1 à C4, indolyle ou l'hydrogène ;
R3 et R5 représentent, indépendamment, l'hydrogène, un groupe OH, alkoxy en C1 à C5, halogéno, -O(alkyle en C1 à C4)phényle, R11CO2R7, alkyle en C1 à C4, N(R6)2, NH(CO)CH3, -X(CH2)nR8, -X-R9-Y, pyridyle, phényle ou S(O)q(alkyle en C1 à C5) ;
R4 représente l'hydrogène, un groupe OH, alkoxy en C1 à C5, halogéno, alkyle en C1 à C4, N(R6)2, NH(CO)CH3 ou S(O)q(alkyle en C1 à C5) ;
Z1, Z2 et Z3 représentent, indépendamment, un groupe X-R9-Y, benzyle, l'hydrogène, un groupe OH, alkoxy en C1 à C5, -N(R6)2, S(O)q(alkyle en C1 à C8), NHCOR6, X(CH2)nR8 ou halogéno, ou bien Z1 et Z2, conjointement, peuvent représenter un groupe -O-A-O- sur des atomes de carbone contigus ;
P1 et P2 représentent, indépendamment, l'hydrogène, un groupe CO2H ou tétrazole ;
Ar représente un groupement de formule (a) ou (b) ou un groupe pyridyle ; et
X représente un groupe (CH2)n ou l'oxygène.
R3 représente l'hydrogène, un groupe -X(CH2)nR8 ou R11CO2R7 ;
R4 et R5 représentent, indépendamment, l'hydrogène, un groupe OH, alkoxy en C1 à C5, S(alkyle en C1 à C5), F, Br, alkyle en C1 à C3 ou NH2 ; et
Z1 et Z3 représentent l'hydrogène et Z2 représente l'hydrogène, un groupe OH, alkoxy en C1 à C5, halogéno, X(CH2)nR8, NH2, benzyle ou NH(CO)CH3, ou bien Z1 et Z2, conjointement, peuvent représenter un groupe -O-A-O- sur des atomes de carbone contigus.
R1 représente un groupement de formule (b) ;
A représente un groupe CH2, B représente -O- ;
il n'existe aucune double liaison facultative ;
R1 et XR2 sont en positions trans par rapport à P1 ;
Z2 représente un groupe OH, alkoxy en C1 à C5, -OCH2CH2CH3 ou l'hydrogène ;
Z1 représente l'hydrogène ;
R3 repréente l'hydrogène, un groupe XAr, X(CH2)qCO2H, X(CH2)qCONR7SO2R11 ou CH=CHCO2H ;
R4 représente l'hydrogène ou un groupe alkoxy en C1 ou C2 ; et
R5, R10 et P2 représentent l'hydrogène.
dans laquelle Z1, Z2, Z3 et R1 sont des groupes répondant aux définitions suivant la revendication 1 ou des groupes pouvant être convertis en ceux-ci, et X représente un groupe alkyle en C1 à C5, avec un composé organique de magnésium de formule (12) :
R2(CH2)n-MgBr (12)
dans laquelle R2 représente un groupe défini dans la revendication 1 ou un groupe pouvant être converti en celui-ci, dans un solvant convenable, ce qui donne un composé de formule (13) :
qui est réduit et ensuite, lorsque cela est désiré ou nécessaire, subit :
a) une insertion de R10 (lorsqu'il est autre que l'hydrogène) par addition de conjugué ; et/ou
b) une alkylation ou acylation, ce qui donne des composés dans lesquels P1 et P2 sont autres que des groupes CO2H ; et/ou
c) une conversion des groupes R1, R2, Z1, Z2 et Z3 en d'autres groupes R1, R2, Z1, Z2 et Z3 ; ce qui donne un composé de formule (I).