WO2001081335A1 - Pyrimidine-sulfonamides agissant comme antagonistes de l'endotheline - Google Patents

Pyrimidine-sulfonamides agissant comme antagonistes de l'endotheline Download PDF

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WO2001081335A1
WO2001081335A1 PCT/EP2001/004136 EP0104136W WO0181335A1 WO 2001081335 A1 WO2001081335 A1 WO 2001081335A1 EP 0104136 W EP0104136 W EP 0104136W WO 0181335 A1 WO0181335 A1 WO 0181335A1
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lower alkyl
phenoxy
methoxy
pyridine
formula
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PCT/EP2001/004136
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English (en)
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Martin Bolli
Christoph Boss
Martine Clozel
Walter Fischli
Thomas Weller
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Actelion Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel tetra-substituted pyrimidines 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 antagonists.
  • Endothelins are 21 -amino acid peptides produced and active in almost all tissues (Yanagisawa 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 ET B 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 ETB receptor from smooth muscle cells exerts vasoconstricting actions (fpumner MJ et al.: Brit J Pharmacol (1992) 107:858).
  • ETA 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 ETB receptors were used.
  • Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu V., 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 2 h, the membranes were filtered on filterplates containing GF/C filters (Unifilterplates from Canberra Packard S.A. Zurich, Switzerland).
  • IC 50 was calculated as the concentration of antagonist inhibiting 50 % of the specific binding of ET-1.
  • Example 60 117 4850
  • Example 61 101 6320
  • Example 93 199 1110 Example 126 4640 2840
  • 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 rings (ETB receptors).
  • E A receptors endothelin-1 on rat aortic rings
  • EB receptors sarafotoxin S6c on rat tracheal rings
  • Each ring was suspended in a 10 ml isolated organ bath filled with Krebs- Henseleit solution (in mM; NaCl 115, KCI 4.7, MgSO 4 1.2, KH 2 PO 4 1.5, NaHCO 3 25, CaCI 2 2.5, glucose 10) kept at 37° 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 EC 50 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 two-fold shift in the EC 50 value.
  • 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, pain as well as other diseases presently known to be related to endothelin.
  • the compounds can be administered orally, rectally, parenterally, e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol.
  • parenterally e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol.
  • applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
  • Preferred applications are intravenous, intra-muscular, or oral administrations as well as eye drops.
  • 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 tetra-substituted pyrimidines of the general formula I, ⁇ I
  • R 1 represents aryl; heteroaryl;
  • R 3 represents 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; aryl; heteroaryl;
  • R 4 represents hydrogen; halogen; trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; lower alkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy- lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl-amino; aryl; aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower al
  • X represents oxygen; sulfur; NH; CH 2 or a bond;
  • R a and R c independently represent hydrogen or lower alkyl
  • R b represents hydrogen; lower alkyl; aryl; aryl-lower alkyl; heteroaryl; heteroaryl- lower alkyl;
  • n 1 , 2, 3, 4, 5 or 6
  • 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, isopropyi, 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 acetyi, propanoyl and butanoyl.
  • Lower alkenylen means e.g.vinylen, propenylen and butenylen.
  • Lower alkenyl and lower alkynyl means groups like ethylen, propylen, butylen, 2-methyl-propenyl, and ethinylen, propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc.
  • Lower alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like.
  • the expression cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 7 carbon atoms , e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkoxy- lower alkyl and lower alkenylen groups.
  • heterocyclyl means saturated or unsaturated ( but not aromatic ) four, 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 adequatly substituted with lower alkyl, amino, 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 and a nitrogen 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.
  • rings may be substituted with lower alkyl, lower alkenyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy, trifluoromethoxy, trifluoromethyl, carboxyl, carboxamidyl, thioamidyl, amidinyl, lower alkyl-methanoylate, cyano, hydroxy-lower alkyl, lower alkyl-oxy-lower alkyl or another heteroaryl- (preferrably tetrazolyl) or heterocyclyl-ring (preferrably 5- oxo-1 ,2,4-oxadiazolyl, 5-oxo-1,2,4-triazolyl, 5-oxo-1 ,2,4-thiadiazolyl, 5-thioxo- 1 ,2,4-oxadiazolyl or 2-oxo-1,2,3,5-oxathiadiazolyl).
  • heteroaryl- preferrably tetrazolyl
  • heterocyclyl-ring
  • aryl represents unsubstituted as well as mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphthyl rings which may be substituted with aryl, halogen, hydroxy, lower alkyl, lower alk ⁇ nyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyl-lower alkyl-oxy, lower alkenylen, lower aikylenoxy, lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy- lower alkyl-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl,
  • Especially preferred compounds are compounds of general formula I wherein R 3 represents phenyl or mono-substituted phenyl substituted with lower alkyloxy, especially methoxy and X represents oxygen.
  • a second group of especially preferred compounds of general formula I are the compounds wherein R 3 represents phenyl or mono-substituted phenyl substituted with lower alkyl, especially methyl, or lower alkoxy, especially methoxy and X represents a bond.
  • 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 and also in the meso-form.
  • 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, pain, 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, in nasal form like sprays or rectically in form of suppositories.
  • These compounds may also be administered in intramuscular, parenterai 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, anti oxidants 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.; Angiotensin II antagonists; Diuretics like hydrochlorothiazide, chlorothiazide, acetolamide, bumetanide, furosemide, metolazone,
  • the dosage may vary within wide limits but should be adapted to the specific situation.
  • the dosage given daily in oral form should 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 in 1 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.
  • Preferred compounds are compounds of formula II
  • R 1 and R 4 are as defined in general formula I above, and pharmaceutically acceptable salts of compounds of formula
  • R 1 and R 4 are as defined in general formula I above and R 5 represents hydrogen, lower alkyl or a phenylring and pharmaceutically acceptable salts of compounds of formula III. Also preferred are compounds of formula IV
  • R 2 and R 4 are as defined in general formula I above and R 6 represents hydrogen, methyl or isopropyi, and pharmaceutically acceptable salts of compounds of formula IV.
  • Another especially preferred group of compounds are compounds of formula V
  • R 6 is as defined in formula IV above
  • R 2 is as defined in general formula I above
  • R 7 represents heteroaryl or heterocyclyl, and pharmaceutically acceptable salts thereof.
  • Especially preferred compounds among the group of compounds of formula V are those wherein R 2 represents allyl or propargyl.
  • R 1 , R 2 , R 3 and R 4 are as defined in formula I above, and pharmaceutically acceptable salts of compounds of formula VI.
  • R 1 , R 2 and R 4 are as defined in general formula I above, and pharmaceutically acceptable salts of compounds of formula VII.
  • Preferred compounds are:
  • the 2-substituted malonic esters 4 were prepared according to published procedures [2] by reacting dimethylchloromalonate (3) with the appropriate alcohol 5 in acetone and potassium carbonate as base. The compounds 4 were dissolved in methanoi and sodium methylate was added and stirring was continued for about 30 min followed by the addition of an amidine derivative 2. Stirring at ambient temperature was continued for another 8 h. After acidic work up the 4,6- dihydroxypyrimidines 6 could be isolated in yields of 70 to 90% [2]. Compounds 6 or the tautomeric form thereof were transformed into the dichloro derivatives 7 with phosphorous oxychloride in the presence of N,N-dimethylaniline at elevated temperatures (60-120°C) in yields of 40 to 75% [3].
  • the pyrimidine derivatives 10 are the central intermediates which can be transformed to the desired final products 12 by reaction with a sodium salt of an alcohol 11 in a mixture of THF / DMF at temperatures of 20 - 80°C. [1] W. G ⁇ hring, J. Schildknecht, M. Federspiel; Chimia, 1996, 50, 538 - 543.
  • Reference Example 9 a) A solution of 32.75 g of dimethyl-(o-methoxyphenoxy)malonate (Reference Example 1 b) in 250 ml of methanoi was cooled to 0°C. 20.0 g sodium methylate was added portionwise and upon completion of the addition the mixture was stirred at room temperature for 6 h. Then 25.0 g of morpholinoformamidine hydrobromide was added and stirring was continued for 72 h. The solvent of the beige suspension was evaporated and the residue was washed twice with 150 ml of diethyl ether. The remaining powder was dissolved in 200 ml of water. Upon adjusting the pH to 4 with 50 ml of acetic acid a. precipitate formed.
  • 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.
  • Reference Example 15 a) To a solution of 5.17 g of sodium in 200 ml of methanoi 21.1 g of dimethyl-(2- methoxyphenoxy)malonate was added and the mixture was stirred at r.t. for 30 min. To the slurry 12.0 g of cyclopropylamidine hydrochloride was added. The mixture was stirred at r.t. for 22 h. Eventually, the solvent was removed in vacuo. The remaining residue was suspended in 250 ml of diethyl ether. The ether was decanted and the remaining solid was dissolved in 250 ml of water. The solution was acidified with 25% aqueous hydrochloric acid.

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Abstract

L'invention concerne de nouvelles pyrimidines tetrasubstituées et leur utilisation comme principes actifs pour la préparation de compositions pharmaceutiques. L'invention concerne également des procédés pour la préparation de ces composés, des compositions pharmaceutiques contenant un ou plusieurs de ces composés et en particulier l'utilisation de ces compositions comme antagonistes du récepteur de l'endothéline. Ces composés sont représentés par la formule suivante :
PCT/EP2001/004136 2000-04-20 2001-04-11 Pyrimidine-sulfonamides agissant comme antagonistes de l'endotheline WO2001081335A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
WO2004078104A2 (fr) * 2003-03-06 2004-09-16 Speedel Pharma Ag Nouveau medicament
WO2007031501A2 (fr) * 2005-09-12 2007-03-22 Speedel Pharma Ag Pyridylsulfonamidyl-pyrimidines utiles dans la prevention d'un rejet de greffe de vaisseau sanguin
US7531547B2 (en) 2005-09-01 2009-05-12 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7776872B2 (en) 2005-09-01 2010-08-17 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7799796B2 (en) 2005-09-01 2010-09-21 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7858632B2 (en) 2004-03-05 2010-12-28 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
WO2009095933A3 (fr) * 2008-01-10 2011-06-30 Msn Laboratories Limited Procédé perfectionné et nouveau pour la préparation de bosentan
US8268847B2 (en) 2006-08-29 2012-09-18 Actelion Pharmaceuticals, Ltd. Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
WO2021047407A1 (fr) * 2019-09-10 2021-03-18 四川科伦博泰生物医药股份有限公司 Composé biaryle, composition pharmaceutique le comprenant, procédé de préparation correspondant et utilisation associée

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EP1693372A1 (fr) * 2000-12-18 2006-08-23 Actelion Pharmaceuticals Ltd. Nouveaux sulfamides et leur utilisation comme antagoniste du récepteur d'endotheline
US7285549B2 (en) 2000-12-18 2007-10-23 Actelion Pharmaceuticals Ltd. Sulfamides and their use as endothelin receptor antagonists
WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
US7094781B2 (en) 2000-12-18 2006-08-22 Actelion Pharmaceuticals Ltd. Sulfamides and their use as endothelin receptor antagonists
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WO2004078104A3 (fr) * 2003-03-06 2004-10-28 Speedel Dev Ag Nouveau medicament
WO2004078104A2 (fr) * 2003-03-06 2004-09-16 Speedel Pharma Ag Nouveau medicament
AU2009225323B2 (en) * 2003-03-06 2011-11-24 Speedel Pharma Ag Pyridylsulfonamido pyrimidines for treating diabetic nephropathy
AU2004216858B2 (en) * 2003-03-06 2009-07-16 Speedel Pharma Ag Pyridylsulfonamido pyrimidines for treating diabetic nephropathy
KR101099189B1 (ko) * 2003-03-06 2011-12-27 스페델 파르마 아게 당뇨병성 신장병증을 치료하기 위한 피리딜술폰아미도피리미딘
US9556127B2 (en) 2004-03-05 2017-01-31 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US8846705B2 (en) 2004-03-05 2014-09-30 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US7858632B2 (en) 2004-03-05 2010-12-28 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US7531547B2 (en) 2005-09-01 2009-05-12 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7776872B2 (en) 2005-09-01 2010-08-17 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7799796B2 (en) 2005-09-01 2010-09-21 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
WO2007031501A3 (fr) * 2005-09-12 2007-04-26 Speedel Pharma Ag Pyridylsulfonamidyl-pyrimidines utiles dans la prevention d'un rejet de greffe de vaisseau sanguin
JP2009507890A (ja) * 2005-09-12 2009-02-26 シュペーデル・ファルマ・アーゲー 血管移植片機能不全の予防のためのピリジルスルホンアミジル−ピリミジン類
WO2007031501A2 (fr) * 2005-09-12 2007-03-22 Speedel Pharma Ag Pyridylsulfonamidyl-pyrimidines utiles dans la prevention d'un rejet de greffe de vaisseau sanguin
US8268847B2 (en) 2006-08-29 2012-09-18 Actelion Pharmaceuticals, Ltd. Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
WO2009095933A3 (fr) * 2008-01-10 2011-06-30 Msn Laboratories Limited Procédé perfectionné et nouveau pour la préparation de bosentan
WO2021047407A1 (fr) * 2019-09-10 2021-03-18 四川科伦博泰生物医药股份有限公司 Composé biaryle, composition pharmaceutique le comprenant, procédé de préparation correspondant et utilisation associée
CN114096525A (zh) * 2019-09-10 2022-02-25 四川科伦博泰生物医药股份有限公司 联芳基类化合物，包含其的药物组合物，其制备方法及其用途
CN114096525B (zh) * 2019-09-10 2023-10-13 四川科伦博泰生物医药股份有限公司 联芳基类化合物，包含其的药物组合物，其制备方法及其用途

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