EP1244637A1 - Derives de butynediol - Google Patents

Derives de butynediol

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Publication number
EP1244637A1
EP1244637A1 EP00991788A EP00991788A EP1244637A1 EP 1244637 A1 EP1244637 A1 EP 1244637A1 EP 00991788 A EP00991788 A EP 00991788A EP 00991788 A EP00991788 A EP 00991788A EP 1244637 A1 EP1244637 A1 EP 1244637A1
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EP
European Patent Office
Prior art keywords
hydroxy
lower alkyl
substituted
pyrimidinyl
phenyl
Prior art date
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EP00991788A
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German (de)
English (en)
Inventor
Martin Bolli
Christoph Boss
Martine Clozel
Walter Fischli
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Priority to EP00991788A priority Critical patent/EP1244637A1/fr
Priority claimed from PCT/EP2000/012743 external-priority patent/WO2001046156A1/fr
Publication of EP1244637A1 publication Critical patent/EP1244637A1/fr
Withdrawn legal-status Critical Current

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Definitions

  • the present invention relates to novel butyne diol derivatives of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I and especially their use as endothelin receptor antagonists.
  • Endothelins are 21 -amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411. Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46:328).
  • ET A , ET B Two endothelin receptors have been cloned and characterized in mammals (ET A , ET B ) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732).
  • the ET A receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohlstein EH et al.: Drug Dev Res (1993) 29:108).
  • the ETB receptor has equivalent affinity for the 3 endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991 ) 178:248).
  • This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain.
  • ET B receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ET B receptor from smooth muscle cells exerts vasoconstricting actions (Sumner MJ et al.: Brit J Pharmacol (1992) 107:858).
  • ET A and ET B receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.
  • ET-1 A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma.
  • endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.
  • membranes of CHO cells expressing human recombinant ETA or ET B receptors were used. Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu et al, FEBS Lett 1993; 334:210).
  • the assay was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, including 25 mM MnCI 2 , 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates.
  • Membranes containing 0.5 ug protein were incubated for 2 h at 20°C with 8 pM [ 125 I]ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1 , respectively. After two h, the membranes were filtered on filterplates containing GF/C filters (Unifilterplates from Canberra Packard S.A. Zurich, Switzerland).
  • the functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ET A receptors) and of the contraction induced by sarafotoxin S6c on rat tracheal (ET B receptors).
  • E A receptors endothelin-1 on rat aortic rings
  • E B receptors sarafotoxin S6c on rat tracheal
  • Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCI 115, KCI 4.7, MgSO 4 1.2, KH 2 P0 4 1.5, NaHCO 3 25, CaCI 2 2.5, glucose 10) kept at 37°C and gassed with 95% O 2 and 5% CO 2 .
  • the rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA, Paris, France).
  • the rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea) were added after a 10 min incubation with the test compound or its vehicle.
  • the functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC50 induced by different concentrations of test compound.
  • EC 50 is the concentration of endothelin needed to get a half-maximal contraction
  • pA 2 is the negative logarithm of the antagonist concentration which induces a twofold shift in the EC 50 value.
  • Example 58 7.57
  • Example 59 7.70
  • the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
  • diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
  • diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension.
  • Atherosclerosis prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
  • the compounds can be administered orally, rectally, parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as ophthalmic preparation or administered as aerosol.
  • parenterally e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as ophthalmic preparation or administered as aerosol.
  • examples of applications are capsules, tablets, oral administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
  • Preferred applications are intravenous, intra-muscular, eye drops or oral administrations.
  • the dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1 - 50 mg / kg body weight per day are considered.
  • the preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
  • the present invention relates to butyne diol derivatives of the general formula
  • R 1 represents phenyl; mono-, di- or tri-substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; heterocyclyl; five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms which may be mono- or di-substituted with hal
  • R 2 represents hydrogen; lower alkyl; trifluoromethyl; phenyl; mono-, di- or tri- substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy- cycloalkyl; heterocyclyl; five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms which may be mono-
  • R a represents lower alkyl; cycloalkyl; trifluoromethyl; phenyl; mono-, di- or tri- substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy- cycloalkyl; heterocyclyl; five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atom
  • R 3 represents hydrogen, lower alkyl, phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, amino, lower alkylamino, amino-lower alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl, formyl; benzofuranyl; heteroaryl; mono- or disubstituted heteroaryl substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, amino, lower alkylamino, trifluoromethyl, halogen, hydroxy, hydroxy-lower alkyl, cyano, carboxyl;
  • R 4 represents hydrogen, halogen, trifluoromethyl, lower alkyl, lower cycloalkyl, lower alkyloxy, lower cycloalkyloxy, lower alkylthio, lower alkylthio-lower alkyl, hydroxy-lower alkyl, lower alkyl-oxy-lower alkyl, hydroxy-lower alkyl-oxy-lower alkyl, amino-lower alkyl, lower alkyl-amino-lower alkyl, amino, lower alkyl- amino, di-lower alkyl-amino; phenyl; mono-, di- or tri-substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six- membered ring, lower alkenyl, lower alkenyl
  • X represents oxygen; sulfur; NH or a bond
  • lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms.
  • Examples of lower alkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy.
  • Lower alkylendioxy-groups are preferably methylen-dioxy, ethylen-dioxy, propylen- dioxy and butylen-dioxy- groups.
  • Examples of lower alkanoyl-groups are acetyl, propanoyl and butanoyl .
  • Lower alkenylen means e.g.vinylen, propenylen and butenylen.
  • Lower alkenyl and lower alkynyl means groups like ethylen, propylen, butylen, tert.-butylen(2-methyl-propenyl), and acetylenyl, propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc.
  • Lower alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like.
  • cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 6 carbon atoms , e.g.
  • heterocyclyl means saturated or unsaturated ( but not aromatic ) five-, six- or seven- membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be substituted with lower alkyl, amino, halogen, nitro, hydroxy, lower alkoxy, e.g.
  • heteroaryl means six- membered aromatic rings containing one to four nitrogen atoms, benzofused six-membered aromatic rings containing one to three nitrogen atoms, five- membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, benzo- fused five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, five membered aromatic rings containig an oxygen and nitrogen atom and benzo fused derivatives thereof, five Crowd aromatic rings containing a sulfur, nitrogen or oxygen atom and benzo fused derivatives thereof, five- membered aromatic rings containing two nitrogen atoms and benzo fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring, e.g.
  • aryl represents mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphthyl rings which may be substituted with phenyl, halogen, hydroxy, lower alkoxy, lower alkyl, trifluoromethyl, lower alkenyloxy, trifluoromethoxy, cyclopropyl, hydroxy-cyclopropyl, lower alkylenoxy or lower alkylendioxy.
  • salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p- toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc.
  • hydrohalogenic acids e.g. hydrochloric or hydrobromic acid
  • an inorganic base like an alkali or earth alkali base, e.
  • the compounds of the general formula I might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates.
  • the present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization etc.
  • the described compounds of the general formula I and their pharmaceutically acceptable salts may be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
  • diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
  • diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension.
  • Atherosclerosis prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
  • compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectically in form of suppositories.
  • enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions
  • nasal form like sprays or rectically in form of suppositories.
  • These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions.
  • compositions may contain the compounds of formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
  • vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used.
  • solutions and sirups e.g. water, polyols, saccharose, glucose etc. are used.
  • injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc.
  • Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats ), liquid or half-liquid polyols etc.
  • compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, antioxidants etc.
  • the compounds of formula I may also be used in combination with one or more other therapeutically useful substances e.g. - and ⁇ -blockers like Phentolamine, Phenoxybenzamine, Atenolol, Propranolol, Timolol, Metoprolol, Carteolol etc.; Vasodilators like Hydralazine, Minoxidil, Diazoxide, Flosequinan etc.; Calcium-antagonists like Diltiazem, Nicardipine, Nimodipine, Verapamil, Nifedipine etc.; ACE-inhibitors like Cilazapril, Captopril, Enalapril, Lisinopril etc.; Potassium activators like Pinacidil etc.
  • - and ⁇ -blockers like Phentolamine, Phenoxybenzamine, Atenolol, Propranolol, Timolol, Metoprolol, Carteolol etc.
  • Angiotensin II antagonists include Hydrochlorothiazide, Chlorothiazide, Acetolamide, Bumetanide, Furosemide, Metolazone, Chlortalidone etc.; Sympatholitics like Methyldopa, Clonidine, Guanabenz, Reserpine etc.; and other therapeutics which serve to treat high blood pressure or any cardiac disorders.
  • the dosage may vary within wide limits but should be adapted to the specific situation.
  • the dosage given in oral form should daily be between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg.
  • the dosage should be administered preferably in1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.
  • a preferred group of compounds are compounds of formula I wherein R 1 , R 2 , and R 4 are as defined above, and wherein
  • R 3 represents phenyl; mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, trifluoromethoxy, halogen;
  • X represents oxygen or a single bond
  • Another preferred group of compounds are compounds of formula II
  • R 2 , R 3 , R 4 , and X are as defined in formula I above, and R 5 represents lower alkyl, and pharmaceutically acceptable salts of compounds of formula II.
  • R >1 , o R3 , D R 4 , and X are as defined in formula I above, and R 6 , R 7 , and R 8 , each and independently represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkynyloxy, halogen, trifluoromethyl, trifluoromethoxy or lower alkylthio;
  • R 1 , R 3 , R 4 , R a and X are as defined in formula I above,
  • R 1 , R 3 , R 4 , and X are as defined in formula I above, and wherein R 2 represents lower alkyl
  • Another group of preferred compounds are the compounds described as final products in the Examples 1 to 96 as given below, and pharmaceutically acceptable salts thereof.
  • the compounds of the general formula I are prepared from compounds of the formula V by one of the two pathways given below.
  • Compounds of the formula VII can be prepared by reacting 2-butyne-1 ,4-diol with R 2 -Y in the presence of a base (e.g. an alkali metal hydroxide, an alkali metal alkoxide, sodium hydride, etc.) in a solvent such as DMSO, DMF, THF, pyridine, water, etc. (e.g. Tetrahedron Letters 38 (1997), 7887-7890; Bull. Chem. Soc. Jpn. 28 (1955), 80-82; J. Org. Chem. 18 (1953), 1601-1606).
  • a base e.g. an alkali metal hydroxide, an alkali metal alkoxide, sodium hydride, etc.
  • a solvent such as DMSO, DMF, THF, pyridine, water, etc.
  • Compounds of the formula VII can also be prepared by reacting a suitably hydroxy-protected 1-chloro-4-hydroxy-2-butyne with an alkoxide, followed by cleavage of the protecting group as described in the literature (e.g. Bull. Chim. Soc. 1955, 502; J. Org. Chem. USSR (Engl. Transl.) 12 (1976), 505- 507; J. Org. Chem. 63 (1998), 4291 -4298).
  • VIII Treatment of VIII with an excess of the appropiate sulfonamide potassium salt in the presence or absence of a base (e.g. triethylamine, H ⁇ nig's base) in a solvent (e.g DMF, DMSO) at room temperature furnished the desired compounds V.
  • a base e.g. triethylamine, H ⁇ nig's base
  • a solvent e.g DMF, DMSO
  • Compounds VIII could be prepared by treating the corresponding compounds IX (or tautomeric forms thereof) at elevated temperatures (30-120°C) with a chlorinating agent such as POCI 3 , PCI 5 , or mixtures thereof, etc. each in the presence or absence of a base such as N,N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Bioorg. Med. Chem. Lett., 7 (1997), 2223 - 2228; J. Med. Chem., 41 (1998), 3793 - 3803; J. Chem. Soc. 1959, 2214; Bull. Soc. Chim. Fr. 1958, 741-742).
  • a chlorinating agent such as POCI 3 , PCI 5 , or mixtures thereof, etc. each in the presence or absence of a base such as N,N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Bioorg. Med. Chem. Lett.,
  • the compounds IX resulted from condensation of the corresponding amidines X (isolated as hydrochloride salts) with the appropriate malonic ester derivatives XI in the presence of a sodium alkoxide in a solvent such as methanol, ethanol, etc. at room temperature (e.g. Bull. Soc. Chim. Fr. 1960, 1648).
  • amidines X were prepared form the corresponding nitriles XII by treatment of the nitriles XII either with sodium methylate in methanol followed by the addition of ammoniumchloride, or with lithium hexamethyldisilazan followed by the addition of hydrochloric acid in isopropanol (Advanced Organic Chemistry, by J. March, 3 rd edtion, Wiley 1985, p. 803 and references cited therein).
  • the malonic ester derivatives XI were either commercially available or were prepared following the procedures found in the literature (e.g. J. Am. Chem. Soc. 62 (1940), 1154, 1155; ibid. 74 (1952), 4466; J. Chem. Soc. Perkin 1 , 1979, 2382-2386; Collect. Czech. Chem. Comm. 55 (1990), 1278-1289; J. Med. Chem. Chim. Ther. 26 (1991 ), 599-604; Bull. Soc. Chim. Fr. 1973, 2065-2071 ).
  • compounds with one or more optically active carbon atom are resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates in a manner known per se, and, if desired, synthesised compounds of formula I were converted into a pharmaceutically acceptable salt in a manner known per se.
  • DCM dichloromethane
  • MeOH methanol
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone
  • DMAP 4-dimethylaminopyridine
  • DBU 1 ,8- diazabicyclo[5.4.0]undec-7-ene
  • min minutes
  • h hours.
  • 5-isopropyl pyridine-2-sulfonamide potassium salt was prepared according to procedures disclosed in EP 0713875 A1 and Bioorganic & Medicinal Chemistry Letters, 7 (1997), 2223-2228.
  • f) 1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine and 1.43 g of 5-isopropyl pyridine-2-sulfonamide potassium salt were suspended in 20 ml of dry DMF. The mixture was stirred under argon at room temperature and became clear within a few h. After 16 h at room temperature, most of the solvent was removed by evaporation under reduced pressure.
  • the slurry was allowed to cool to room temperature, was then poured onto a mixture of 200 ml of an aqueous solution of 10% citric acid and 200 ml of ethyl acetate. A fine precipitate formed. The precipitate was filtered off, washed with water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were dried over MgSO 4 and the solvent was removed to a volume of about 10 ml. The fine precipitate that formed was collected, washed with ethyl acetate, and combined with the precipitate isolated from the aqueous layer.
  • Example 6 0 a) To a suspension of 2.0 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2- pyrimidinyl)-pyrimidine (Example 4 b) and 2.65 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 3c) in 40 ml of DMF was added 10 ml of DMSO. The mixture became clear and stirring was continued for 16 h at room temperature. Upon pouring the mixture onto 50 ml of 10% citric acid in5 water a white precipitate formed. The precipitate was collected, washed with water and ethyl acetate, and dried.
  • the aqueous layer was extracted with 400 ml of DCM.
  • the combined DCM layers were dried over Na 2 SO 4 and the solvend was removed to a volume of about 100 ml.
  • the remaining solution was filtered over 50 g of silica gel eluting with DCM.
  • the filtrate was evaporated.
  • the resulting residue was suspended in 50 ml of diethyl ether.
  • the solid was filtered off and dried to give 13.85 g of 4,6- dichloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-pyrimidine as a white crystalline powder.
  • Example 16 a A mixture of 10 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine (Example 12b) and 4.8 g of 5-isopropyl pyridine-2-suIfonamide potassium salt (Example 1e) in 100 ml of DMF was stirred at room temperature for 72 h. The solvent was partially removed in vacuo before the mixture was treated with 50 ml of diethyl ether. Under vigorous stirring, the pH of the aqueous phase was adjusted to 3 by adding a 10% aqueous citric acid solution. Stirring was continued for 15 min at 10°C. The precipitate that formed was collected, washed with water and diethtyl ether and dried under high vaccum at 50°C.
  • Example 2c Example 2c was added. After stirring for 2 h, 91 mg of 2-chloropyrimidine was added. Stirring was continued for 42 h at room temperature. The solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous acetic acid and 50 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO and evaporated. The remaining residue was purified by column chromagraphy on silica gel eluting with a gradient of 5-10% of methanol in DCM.
  • Example 27 78 mg of 5-isopropyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o- methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a beige foam starting from 80 mg of 5-isopropyl-N-[6-(4-hydroxy- 2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyI)-4-pyrimidinyl]-2- pyridine sulfonamide (Example 4d) and 55 mg of 5-bromo-2-chloropyrimidine following the procedure given in Example 22.
  • the organic layer was separated and the aqueous layer was extracted two more times with 50 ml of ethyl acetate.
  • the combined organic layers were washed with water and brine, dried over MgSO and evaporated.
  • the remaining residue was purified by column chromagraphy on silica gel eluting with a gradient of 10-20% of ethyl acetate in toluene.
  • the isolated yellow foam was further purified on a preparative silica gel plate.
  • the mixture was diluted with 50 ml of ethyl acetate.
  • the solution was washed twice with 20 ml of water.
  • the aqueous layers were extracted once with ethyl acetate.
  • the combined organic layers were dried over MgSO and evaporated.
  • the residue was purified by column chromatography on silica gel eluting first with hexane : ethyl acetate 1 :1 then with DCM containing 4% of methanol.
  • Example 1g and 10 mg of 4-dimethylaminopyridine in 5 ml of dry chloroform 25 ⁇ l of phenyl isocyanate was added at room temperature. The mixture was heated to 65°C and stirred for 4 h. Eventually, the mixture was diluted with 50 ml of ethyl acetate. The solution was washed twice with 20 ml of water. The aqueous layers were extracted once with ethyl acetate. The combined organic layers were dried over MgSO and evaporated. The residue was purified by column chromatography on silica gel eluting first with hexane : ethyl acetate 1 :1 then with DCM containing 4% of methanol.
  • Example 3 10 mg of DMAP and 25 ⁇ l of phenylisocyanate in 5 ml of chloroform was refluxed for 15 minutes under argon. 1.5 ml of DMF was added and stirring and heating was continued for 16 h. The clear solution was diluted with 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and 2x50 ml of water. The organic phase was dried over MgS0 4 and evaporated.
  • Example 73 To a solution of 570 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o- methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 9) in 15 ml of DCM was added 0.37 ml of DBU, a catalytic amount of DMAP and 70 ⁇ l of morpholine-4-carbonyl chloride. The mixture was stirred at reflux for 16 h before it was evaporated. The residue was partitioned between 75 ml of 10% aqueous citric acid and 75 ml of ethyl acetate.
  • Example 91 The compound was purified by column chromatography on silica gel eluting with DCM containing 0-2.5% of methanol followed by chromatography on prep, tic-plates with DCM containing 5% of methanol. The resulting oil was dissolved in 10 ml of diethyl ether and treated with pentane.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de butynediol représentés par la formule générale (I) ainsi que l'utilisation de ceux-ci en tant qu'ingrédient actif pour la préparation de compositions pharmaceutiques. L'invention porte également sur des aspects connexes, notamment des procédés permettant de préparer ces composés, des compositions pharmaceutiques contenant un ou plusieurs composés répondant à la formule générale (I), et en particulier l'utilisation de ceux-ci en tant qu'antagonistes de l'endothéline.
EP00991788A 1999-12-22 2000-12-14 Derives de butynediol Withdrawn EP1244637A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP00991788A EP1244637A1 (fr) 1999-12-22 2000-12-14 Derives de butynediol

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP9910276 1999-12-22
WOPCT/EP99/10276 1999-12-22
EP00991788A EP1244637A1 (fr) 1999-12-22 2000-12-14 Derives de butynediol
PCT/EP2000/012743 WO2001046156A1 (fr) 1999-12-22 2000-12-14 Derives de butynediol

Publications (1)

Publication Number Publication Date
EP1244637A1 true EP1244637A1 (fr) 2002-10-02

Family

ID=26070392

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00991788A Withdrawn EP1244637A1 (fr) 1999-12-22 2000-12-14 Derives de butynediol

Country Status (1)

Country Link
EP (1) EP1244637A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0146156A1 *

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