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WO1997002265A1 - ANTAGONISTES DE l'ENDOTHELINE BUTENOLIDIQUE - Google Patents

ANTAGONISTES DE l'ENDOTHELINE BUTENOLIDIQUE Download PDF

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Publication number
WO1997002265A1
WO1997002265A1 PCT/US1996/010651 US9610651W WO9702265A1 WO 1997002265 A1 WO1997002265 A1 WO 1997002265A1 US 9610651 W US9610651 W US 9610651W WO 9702265 A1 WO9702265 A1 WO 9702265A1
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WO
WIPO (PCT)
Prior art keywords
substituted
phenyl
benzyl
unsubstituted
furan
Prior art date
Application number
PCT/US1996/010651
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English (en)
Inventor
William Chester Patt
Bill R. Reisdorp
Joseph Thomas Repine
Original Assignee
Warner-Lambert Company
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Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to US08/981,059 priority Critical patent/US5922759A/en
Priority to AU63888/96A priority patent/AU6388896A/en
Publication of WO1997002265A1 publication Critical patent/WO1997002265A1/fr
Priority to US09/247,534 priority patent/US6017951A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride

Definitions

  • the present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceu ⁇ tical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction and myocardial ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes.
  • the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma.
  • Endothelin is involved in many human disease states.
  • SAH subarachnoid hemorrhage
  • FR 139317 significantly inhibited the vasoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Nirei H., et al., _____________ 1993;52:1869) .
  • BQ-485 also significantly inhibited the vasoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Yano, et al. , Biochem Biophvs. Res Co ⁇ minn.. 1993; 195:969).
  • Ro 46-2005 (Clozel M. , et al. , Nature.
  • Endothelin-1 (ET-1) , a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs).
  • ET antibody In vivo studies with ET antibodies have been reported in disease models. Left coronary artery ligation and reperfusion to induce myocardial infarction in the rat heart, caused a 4- to 7-fold increase in endogenous endothelin levels. Administra ⁇ tion of ET antibody was reported to reduce the size of the infarction in a dose-dependent manner (Watanabe T., et al., "Endothelin in Myocardial Infarction," Nature. (Lond.) 1990;344:114) . Thus, E” may be involved in the pathogenesis of congestive heart failure and myocardial ischemia (Margulies K.B., et al. , "Increased Endothelin in Experimental Heart Failure, " Circulation. 1990;82:2226) .
  • the effec- tiveness and specificity of the anti-ET antibody were confirmed by its capacity to prevent renal deteriora ⁇ tion caused by a single bolus dose (150 pmol) of synthetic ET, but not by infusion of angiotensin II, norepinephrine, or the thromboxane A 2 mimetic U-46619 in isolated kidneys (Perico N., et al. , "Endothelin Mediates the Renal Vasoconstriction Induced by Cyclosporine in the Rat," J. Am. Soc. Nephrol .. 1990.1:76) .
  • Wistar-Kyoto rats there were no significant changes in these parameters (Ohno A., Effects of Endothelin-Specific Antibodies and Endothelin in Spontaneously Hypertensive Rats," J. Tokyo Women's Med. ______., 1991.61:951).
  • ET A and ET B The distribution of the two cloned receptor subtypes, termed ET A and ET B , have been studied extensively (Arai H., et al. , Nature. 1990; 348 :730, Sakurai T., et al . , Nature. 1990;348 :732) .
  • the ET A or vascular smooth muscle receptor, is widely distributed in cardiovascular tissues and in certain regions of the brain (Lin H.Y., et al. , Proc. Natl . Acad. Sci.. 1991;88:3185) .
  • the ET B receptor originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells, although it is not known if the ET B receptors are the same from these sources .
  • the human ET receptor subtypes have been cloned and expressed (Sakamoto A., et al., B ochem. Biophys . Res. Chem.. 1991;178: 656, Hosoda K., et al. , FEBS Lett.. 1991;287 :23) .
  • the ET A receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET B receptor in the initial vasodilatory response to ET (Takayanagi R. , et al.
  • selective ET B agonists caused only vasodilation in the rat aortic ring, possibly through the release of EDRF from the endothelium (ibid) .
  • selective ET B agonists for example, the linear analog ET[1, 3,11, 15-Ala] and truncated analogs ET[6-21, 1,3,11,15-Ala] , ET[8-21, 11,15-Ala] , and N-Acetyl- ET[10-21, 11,15-Ala] caused vasorelaxation in isolated, endothelium-intact porcine pulmonary arteries
  • ET analogs are potent vasoconstrictors in the rabbit pulmonary artery, a tissue that appears to possess an ET B , nonselective type of receptor (ibid).
  • Plasma endothelin-1 levels were dramatically increased in a patient with maliunant hemangioendo- thelioma (Nakagawa K. et al. , Nippon Hifuka Gakkai Zasshi . 1990;100:1453-1456).
  • the ET receptor antagonist BQ-123 has been shown to block ET-1 induced bronchoconstriction and tracheal - 6 - smooth muscle contraction in allergic sheep providing evidence for expected efficacy in bronchopulmonary diseases such as asthma (Noguchi, et al., Am. Rev. Respir. Pis.. 1992;145(4 Part 2):A858).
  • Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations indicate a role for ET in renal constriction in preeclampsia (Clark B.A., et al., Am. J. Obstet. Gynecol .. 1992;166:962-968).
  • Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlate with the degree of illness and depression of cardiac output (Pittett J., et al., Ann Sur ⁇ .. 1991;213(3) : 262) .
  • the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic shock. This ET A antagonist significantly increased the survival rate in this model (Toshiaki M. , et al. , 20.12.90. EP 0 436 189 Al) .
  • Endothelin is a potent agonist in the liver eliciting both sustained vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output (Gandhi C.B., et al. , Journal of Biological Chemistry. 1990;265(29) :17432) .
  • increased levels of plasma ET-1 have been observed in icroalbuminuric insulin-dependent diabetes mellitus patients indicating a role for ET in endocrine disorders such as diabetes (Collier A., et al., Diabetes Care, 1992;15(8) :1038) .
  • ET A antagonist receptor blockade has been found to produce an antihypertensive effect in normal to low renin models of hypertension with a time course similar to the inhibition of ET-1 pressor responses (Basil M.K., et al., J. Hypertension. 1992; 10(Suppl 4): S49).
  • the endothelins have been shown to be arrhythmo- genic, and to have positive chronotropic and inotropic effects, thus ET receptor blockade would be expected to be useful in arrhythmia and other cardiovascular disorders (Han S.-P., et al. , Life Sci.. 1990;46 : 767) .
  • Circulating and tissue endothelin immunoreactivity is increased more than twofold in patients with advanced atherosclerosis (Lerman A., et al. , New England J. Med.. 1991;325:997-1001). Increased endothelin immunoreactivity has also been associated with Buerger's disease (Kanno K., et al. , _________________
  • Elevated levels of endothelin have also been measured in patients suffering from ischemic heart disease (Yasuda M. , et al. , Amer. Heart J.. 1990;119:801-806) and either stable or unstable angina (Stewart J.T., et al. , Br. Heart J.. 1991;66:7-9).
  • an ET A selective antagonist demonstrated an oral antihypertensive effect (Stein P.D., et al . , "The Discovery of Sulfonamide Endothelin Antagonists and the Development of the Orally Active ET A Antagonist 5- (Dimethylamino) -N- (3,4-dimethyl-5-isoxazolyl) -1- naphthalenesulfonamide, " J. Med. Chem. , 1994;37:329-331.
  • R*L is cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms, phenyl substituted with from 1 to 5 substituents, naphthyl unsubstituted or substituted with from
  • R 2 is alkyl substituted or unsubstituted straight, or branched of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from
  • R 3 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from
  • R 4 is hydroxy or OR 5 ,
  • R 5 is alkyl or substituted alkyl of from 1 to 7 carbon atoms, or (CH 2 ) n OR 5 wherein n is an integer of from 1 to 3; X is 0 or S; with the proviso that when R- ⁇ is monosubstituted phenyl and the substituent is p-methoxy, R 3 is not unsubstituted phenyl, monosubstituted phenyl, or mesityl and with the further proviso when R 2 is alkyl substituted, the substituent is not oxygen at the ⁇ -position to the furanone ring.
  • This application for patent is hereby incorporated by reference.
  • R 2 represents a 1 to 10 carbon alkyl group, 3 to 6 carbon cycloalkyl group, 2 to 10 carbon alkenyl group, 2 to 10 carbon alkynyl group, or phenylalkyl group with a total of less than 10 carbons,
  • R 2 represents a hydrogen atom or hydroxyl group
  • R 3 and R 4 each represent a lower alkyl group
  • R 3 and R 4 together represent an alkylene group with a total of 3 to 6 carbons .
  • the compounds are disclosed as insect repellents .
  • the present invention includes compounds of
  • R ⁇ is cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms, phenyl substituted with from 1 to 5 substituents, naphthyl unsubstituted or substituted with from 1 to 5 substituents, or heteroaryl unsubstituted or substituted with from 1 to 5 substituents;
  • R 2 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from
  • R 3 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms, aryl which is unsubstituted or substituted with from 1 to 5 substituents, heteroaryl which is unsubstituted or substituted with from 1 to 5 substituents;
  • R 4 is alkyl, substituted or unsubstituted with from 1 to 5 substituents; aryl unsubstituted or substituted with from 1 to
  • Preferred compounds of the instant invention are those of Formula I wherein
  • R*L is phenyl substituted with from 1 to 5 substituents, naphthyl unsubstituted or substituted with from 1 to 5 substituents, or heteroaryl unsubstituted or substituted with from 1 to 5 substituents;
  • R 2 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 7 carbon atoms,
  • R 3 is aryl substituted or unsubstituted, heteroaryl substituted or unsubstituted;
  • R 4 is alkyl, unsubstituted or substituted with from 1 to 5 substituents; aryl unsubstituted or substituted with from 1 to 5 substituents; heteroaryl unsubstituted or substituted with from
  • More preferred compounds of the instant invention are those of Formula I wherein R ⁇ is 4-piperonyl
  • R 2 is benzyl
  • R 4 is alkyl, unsubstituted or substituted with from 1 to 5 substituents; aryl unsubstituted or substituted with from 1 to 5 substituents; heteroaryl unsubstituted or substituted with from
  • Still more preferred compounds of the instant invention are selected from: (1-Phenyl-ethyl) -carbamic acid-4-benzo[1, 3]dioxol-
  • Methyl-carbamic acid 4-benzo[l,3]dioxol-5-yl-3- (3,4, 5-trimethoxybenzyl) -2- (4-methoxyphenyl) -5-oxo- 2,5-dihydro-furan-2-yl ester, 3-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5- oxo-3-(3,4,5-trimethoxybenzyl)-2,5-dihydro-furan-2- yloxycarbonylamino] -propionic acid ethyl ester,
  • the compounds of Formula I are useful in the treatment of hypertension, myocardial infarction, diabetes, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, chronic and acute renal failure, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, stroke, head injury, and ischemic bowel disease.
  • a still further embodiment of the present invention is a pharmaceutical composition for administering a therapeutically effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above.
  • the present invention is directed to methods for production of a compound of Formula I .
  • alkyl means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, allyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl.
  • the alkyl group is unsubstituted or substituted by from 1 to 6 substituents selected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, monosubstituted amino, disubstituted amino, formyl, cycloalkyl, sulfonic acid,
  • alkyl, aryl, and heteroaryl are defined as herein.
  • cycloalkyl means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms unless otherwise specified, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
  • the cycloalkyl ring may be unsubstituted or substituted by from 1 to 3 substituents selected from alkyl, cycloalkyl, cycloalkoxy, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, monosubstituted amino, disubstituted amino, formyl, sulfonic acid, carboxyl, nitrile, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl,
  • alkoxy and thioalkoxy are O-alkyl or S-alkyl as defined above for alkyl.
  • Two alkoxy or thioalkoxy groups can be taken together to form a cyclic group such as
  • aryl means an aromatic radical which is a phenyl group, a benzyl group, a naphthyl group, a biphenyl group, a pyrenyl group, an anthracenyl group, or a fluorenyl group and the like, unsubstituted or substituted by 1 to 5 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, nitro, halogen, sulfonic acid, amino, monosubstituted amino, disubstituted amino, formyl, carboxy, nitrile, arylsulfoxyl, alkylsulfoxyl, arylsulfonyl, alkylsulfonyl, 0 0 0 0 0 0
  • heteroaryl means a heteroaromatic radical which is 2-or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1, 2, 3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indoly
  • Halogen is fluorine, chlorine, bromine or iodine.
  • compositions of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts . All of these forms are within the scope of the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, isethionic and the like.
  • salts of amino acids such as lysinate, arginate, and the like and gluconate, galacturonate (see, for example, Berge S.M., et al. , “Pharmaceutical Salts,” Journal of Phar aceutica] Science, 1977;66:1-19).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines .
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, piperazine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S.M., et al. , "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration.
  • the present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds of Formula I are valuable antagonists of endothelin.
  • the tests employed indicate that compounds of the invention possess endothelin antagonist activity.
  • the compounds were tested for their ability to inhibit [ 125 I]-ET-1( [ 125 I]-
  • Endothelin-1 binding in a receptor assay.
  • Selected compounds were also tested for antagonist activity by inhibition of ET-1 stimulated arachidonic acid release and ET-1 stimulated vasoconstriction. The following testing procedures were used (Doherty A.M., et al. , "Design of C-Terminal Peptide Antagonists of Endothelin: Structure-Activity Relationships of ET-1 [16-21, D-His 16 ]", Bioor ⁇ anic and Medicinal Chemistry Letters, 1993;3:497-502).
  • ENDOTHELIN RECEPTOR BINDING ASSAY-A INTACT CELL BINDING OF [ 125 I]-ET-1
  • the cells used were rabbit renal artery vascular smooth muscle cells grown in a 48-well dish (1 cm 2 ) (confluent cells). Growth Media The growth media was Dulbecco's Modified
  • the assay buffer was a medium 199 containing Hanks salts and 25 mM Hepes buffer (Gibco 380-2350AJ) , supplemented with penicillin/streptomycin/fungizone (0.5%) and bovine serum albumin (1 mg/mL).
  • the tissue is made up of 20 mM tris(hydroxy methyl)aminomethane hydrochloride (Trizma) buffer, 2 mM ethylenediaminetetra acetate, 100 ⁇ M phenylmethyl- sulfonyl fluoride.
  • Trizma tris(hydroxy methyl)aminomethane hydrochloride
  • dilute tissue suspension 1/100 (0.1 mL suspension + 9.9 mL tissue buffer), polytron again, and place ice.
  • Protocol 100-mL aliquot of [ 125 I]-ET-1 with 5.2 mL dilution buffer, place on ice until use (final concentration will be 20,000 cpm per tube, or 25 pM) .
  • Protocol Add 50 ⁇ L each of cold [ 125 ]-ET-1 and competing ligand to tubes on ice. Mix in 150 ⁇ L of tissue to each tube, vortex briefly, then tap to force all liquids to bottom (total assay volume - 250 ⁇ L) . Then place the tubes in a 37°C water bath for 2 hours. Add 2.5 mL cold wash buffer (50 mM Trizma buffer) to each tube, filter, and then wash tube with additional 2.5 mL wash buffer and add to filter. Finally, wash filters with an additional 2.5 mL of cold wash buffer.
  • 2.5 mL cold wash buffer 50 mM Trizma buffer
  • Count filters for radioactivity in gamma counter The above process has also been modified by using human recombinant CHO-Kl cells .
  • the tissue used for human ETB was recombinant human ETB receptor expressed in CHO-Kl cells (Chinese hamster ovary cells) .
  • the gene for human ETB receptor was cloned and inserted into the pRc-CMW expression vector, then transfected into CHO-Kl cells by electroporation.
  • membranes (0.7 mg protein) of CHO-Kl cells expressing recombinant human ETB receptor were used.
  • Antagonist activity is measured by the ability of added compounds to reduce endothelin-stimulated arachidonic acid release in cultured vascular smooth muscle cells as arachidonic acid release (AAR) .
  • Arachidonic Acid Loading Media LM is DME/F12 + 0.5% FCS x 0.25 mCi/mL
  • arachidonic acid (Amersham) . Confluent monolayers of cultured rabbit renal artery vascular smooth muscle cells were incubated in 0.5 mL of the LM over 18 hours, at 37°C, in 5% C0 2 .
  • the LM was aspirated and the cells were washed once with the assay buffer (Hank's BSS + 10 mM HEPES + fatty acid-free BSA (1 mg/mL)), and incubated for 5 minutes with 1 mL of the prewarmed assay buffer. This solution was aspirated, followed by an additional 1 mL of prewarmed assay buffer, and further incubated for another 5 minutes. A final 5-minute incubation was carried out in a similar manner. The same procedure was repeated with the inclusion of 10 ⁇ L of the test compound (1 nM to 1 ⁇ M) and 10 ⁇ L ET-1 (0.3 nM) and the incubation was extended for 30 minutes. This solution was then collected, 10 ⁇ L of scintillation cocktail was added, and the amount of [ 3 H] arachidonic acid was determined in a liquid scintillation counter.
  • Denuded rings were mounted in 20 mL organ baths containing Krebs-bicarbonate buffer (composition in mM: NaCl, 118.2; NaHC0 3 , 24.8; KCl, 4.6; MgS0 4 7-H 2 0, 1.2; KH 2 P0 4 , 1.2; CaCl 2 -2H 2 0; Ca-Na 2 EDTA, 0.026; dextrose, 10.0), that was maintained at 37°C and gassed continuously with 5% C0 2 in oxygen (pH 7.4). Resting tension was adjusted to 3.0 g for femoral and 4.0 g pulmonary arteries; the rings were left for 90 minutes to equilibrate.
  • Krebs-bicarbonate buffer composition in mM: NaCl, 118.2; NaHC0 3 , 24.8; KCl, 4.6; MgS0 4 7-H 2 0, 1.2; KH 2 P0 4 , 1.2; CaCl 2 -2H 2 0; Ca-
  • Vascular rings were tested for lack of functional endothelium (i.e., lack of an endothelium- dependent relaxation response to carbachol (1.0 ⁇ M) in norepinephrine (0.03 ⁇ M) contracted rings.
  • the ET antagonists were added 30 minutes prior to adding the agonist and pA 2 values were calculated (Table II).
  • the compounds of Formula I bind to the endothelin receptors ET A (ERBA-A) and ET B (ERBA-B) in the ⁇ M to nM range.
  • the said compounds also reduce endothelin- stimulated arachidonic acid release (AAR) and therefore are functional antagonists.
  • the compounds of Formula I may be prepared as in Scheme I.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intra- cutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally.
  • the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions and/or any of the additions generally regarded as safe.
  • parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents .
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsules, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents .
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg to about 100 mg/kg daily.
  • a daily dose range of about 0.01 mg to about 10 mg/kg is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art.
  • treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day, if desired.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à de nouveaux antagonistes non peptidiques de l'endothéline I, ainsi qu'à leurs procédés de préparation et à leurs compositions pharmaceutiques, qui sont utiles pour le traitement de taux élevés d'endothéline, d'insuffisances rénales aiguës ou chroniques, de l'hypertension, de l'infarctus du myocarde, de l'ischémie myocardique, des spasmes vasculaires cérébraux, de l'ischémie cérébrale, de l'infarctus cérébral, de la cirrhose, du choc septique, de l'insuffisance cardiaque globale, du choc endotoxique, de l'hémorragie sous-arachnoïdienne, de l'arythmie, de l'asthme, de la prééclampsie, des troubles athéroscléreux comprenant la maladie de Raynaud et la resténose, de l'angine, du cancer, de l'hypertension pulmonaire, de la maladie ischémique, des lésions de la muqueuse gastrique, du choc hémorragique, de l'infarctus mésentérique, de l'accident cérébrosvasculaire, de l'hyperplasie prostatique bénigne et du diabète.
PCT/US1996/010651 1995-07-06 1996-06-21 ANTAGONISTES DE l'ENDOTHELINE BUTENOLIDIQUE WO1997002265A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US08/981,059 US5922759A (en) 1996-06-21 1996-06-21 Butenolide endothelin antagonists
AU63888/96A AU6388896A (en) 1995-07-06 1996-06-21 Butenolide endothelin antagonists
US09/247,534 US6017951A (en) 1995-07-06 1999-02-10 Butenolide endothelin antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90495P 1995-07-06 1995-07-06
US60/000,904 1995-07-06

Publications (1)

Publication Number Publication Date
WO1997002265A1 true WO1997002265A1 (fr) 1997-01-23

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Application Number Title Priority Date Filing Date
PCT/US1996/010651 WO1997002265A1 (fr) 1995-07-06 1996-06-21 ANTAGONISTES DE l'ENDOTHELINE BUTENOLIDIQUE

Country Status (3)

Country Link
AU (1) AU6388896A (fr)
WO (1) WO1997002265A1 (fr)
ZA (1) ZA965754B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037985A1 (fr) * 1996-04-10 1997-10-16 Warner-Lambert Company Antagonistes non peptidiques de l'endotheline a meilleure solubilite dans l'eau
WO1997037986A1 (fr) * 1996-04-10 1997-10-16 Warner-Lambert Company Antagoniste de l'endotheline avec groupes lies a l'ether
WO1998042702A1 (fr) * 1997-03-22 1998-10-01 Merck Patent Gmbh Antagonistes du recepteur d'endotheline
WO1999052888A1 (fr) * 1998-04-08 1999-10-21 Washington Odur Ayuko Derives butenolidiques agent anticancereux

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05178706A (ja) * 1991-12-27 1993-07-20 Sumitomo Chem Co Ltd 有害節足動物忌避剤
WO1995005376A1 (fr) * 1993-08-19 1995-02-23 Warner-Lambert Company Derives de 2(5h)furanone, 2(5h)thiophenone et 2(5h)pyrrolone substitues, leur preparation et leur utilisation en tant qu'antagonistes de l'endotheline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05178706A (ja) * 1991-12-27 1993-07-20 Sumitomo Chem Co Ltd 有害節足動物忌避剤
WO1995005376A1 (fr) * 1993-08-19 1995-02-23 Warner-Lambert Company Derives de 2(5h)furanone, 2(5h)thiophenone et 2(5h)pyrrolone substitues, leur preparation et leur utilisation en tant qu'antagonistes de l'endotheline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 9333, Derwent World Patents Index; AN 93-261560, XP002016109 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037985A1 (fr) * 1996-04-10 1997-10-16 Warner-Lambert Company Antagonistes non peptidiques de l'endotheline a meilleure solubilite dans l'eau
WO1997037986A1 (fr) * 1996-04-10 1997-10-16 Warner-Lambert Company Antagoniste de l'endotheline avec groupes lies a l'ether
WO1998042702A1 (fr) * 1997-03-22 1998-10-01 Merck Patent Gmbh Antagonistes du recepteur d'endotheline
WO1999052888A1 (fr) * 1998-04-08 1999-10-21 Washington Odur Ayuko Derives butenolidiques agent anticancereux

Also Published As

Publication number Publication date
AU6388896A (en) 1997-02-05
ZA965754B (en) 1997-01-27

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