WO2002083650A1 - Nouvelles sulfonylamino-pyrimidines - Google Patents

Nouvelles sulfonylamino-pyrimidines Download PDF

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Publication number
WO2002083650A1
WO2002083650A1 PCT/EP2002/003947 EP0203947W WO02083650A1 WO 2002083650 A1 WO2002083650 A1 WO 2002083650A1 EP 0203947 W EP0203947 W EP 0203947W WO 02083650 A1 WO02083650 A1 WO 02083650A1
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phenyl
lower alkyl
compounds
methoxy
phenoxy
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PCT/EP2002/003947
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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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Publication of WO2002083650A1 publication Critical patent/WO2002083650A1/fr

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    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • 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
    • 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
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel sulfonamido-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 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 ( cMillen 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.
  • the ETB 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 (Sumner 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 m 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 5 0 was calculated as the concentration of antagonist inhibiting 50 % of the specific binding of ET-1.
  • the functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ETA receptors) and of the contraction induced by sarafotoxin S6c on rat tracheal rings (ETB receptors).
  • ETA receptors endothelin-1 on rat aortic rings
  • ETB 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; NaCI 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 twofold shift in the EC 50 value.
  • the pA 2 values obtained with compounds of Formula I are given in Table 2.
  • 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 novel sulfonamido-pyrimidines of the general Formula I,
  • R 1 represents aryl; heteroaryl;
  • R 2 represents lower alkyl; cycloalkyl; aryl; heteroaryl; heterocyclyl;
  • R 3 represents phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, trifluoromethyl, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, alkyloxycarbonyl, lower alkanoyl, formyl;
  • R 4 represents hydrogen; trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; lower alkyl-sulfinyl; lower alkylthio; 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; heteroaryl; heterocyclyl; heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino; heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-lower alkyl-thio; heterocyclyl-lower alkyl; cycloalkyl
  • T oxygen or sulfur
  • X represents oxygen; sulfur; CH 2 or a bond;
  • Y represents oxygen; sulfur or -NH-;
  • Q represents -(CH 2 ) k -; -CH 2 -C ⁇ C-CH 2 -;
  • k represents the numbers 2; 3; or 4;
  • Z represents oxygen, or NH
  • lower alkyl or lower alkyloxy means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms.
  • Examples of lower alkyl and lower alkyloxy 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 methylene-dioxy, ethylene-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 ethylene, 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 alkyloxy-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 alkyloxy, 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 termed 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 alkyloxy, 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 (e.g.
  • 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 alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkynyl-lower alkyl-oxy, lower alkenylen, lower alkylenoxy, 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-cyclo
  • 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
  • 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, 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.
  • Another group of preferred compounds are compounds of general Formula I wherein T represents oxygen, and wherein R 1 , R 2 , R 3 , R 4 , A, X, Y, Q, and Z are as defined in general Formula I above, and pharmaceutically acceptable salts thereof.
  • R 3 represents phenyl or mono-substituted phenyl substituted with lower alkyloxy, especially methoxy and X represents oxygen, and pharmaceutically acceptable salts thereof.
  • a third group of especially preferred compounds of general Formula I are the compounds wherein R 3 represents phenyl or mono-substituted phenyl substituted with lower alkyloxy, especially methoxy, and wherein X, Y and Z represent oxygen, and pharmaceutically acceptable salts thereof.
  • Another group of preferred compounds are compounds of Formula II
  • R 1 , R 2 , R 3 , R 4 , A, T, Y, Q, and Z are as defined in general Formula I above, and pharmaceutically acceptable salts of compounds of Formula II.
  • R 3 represents phenyl or mono-substituted phenyl, and wherein Y and Z represent oxygen, and wherein R 1 , R 2 , R 4 , A, T, and Q are as defined in general Formula I above, and pharmaceutically acceptable salts thereof.
  • Preferred compounds are:
  • the desired compounds of general Formula I can be prepared by reacting a compound of the Formula 1 with a carbamoylating agent such as compounds of the Formulas 2, 3, or 4 (commercial source or prepared according to literature procedures e.g. [1]) in the presence or absence of a catalyst such as 4- dimethylaminopyridine, in a solvent such as chloroform or DMF at temperatures between 20 and 120°C.
  • a carbamoylating agent such as compounds of the Formulas 2, 3, or 4 (commercial source or prepared according to literature procedures e.g. [1])
  • a catalyst such as 4- dimethylaminopyridine
  • Formula 2 Compounds of the Formula 1 are prepared by reacting a compound of the Formula 5, wherein G 1 is a reactive residue such as chlorine, with a compound of Formula 6 or a salt thereof in the presence or absence of an additional solvent such as DMF, THF, or DME, at temperatures between 20 and 150°C.
  • G 1 is a reactive residue such as chlorine
  • a compound of Formula 6 or a salt thereof in the presence or absence of an additional solvent such as DMF, THF, or DME, at temperatures between 20 and 150°C.
  • Compounds of Formula 1 may also be prepared by reacting a compound of Formula 7, wherein G 2 represents a reactive group such as alkylsulfonyl or a halogen, with a compound of Formula 8 or a salt thereof.
  • G 2 represents a reactive group such as alkylsulfonyl or a halogen
  • R 4 has to be selected from a group of substituents which are reactive enough (e.g. alcohols, amines, etc.) to replace G 2 .
  • Example of Formula 1 a) NaOMe, MeOH then NH 4 CI or LiN(Si(CH 3 ) 3 ) 2 then HCI/i-PrOH; b) K 2 CO 3 , acetone; c) NaOMe, MeOH; d) POCI 3 ; e) NH 3 /THF then KOtBu, MeOH; f) DMSO; g) NaH, THF, DMF;
  • the amidines 10 were synthesized applying standard methodology [2] by reaction of the appropriate nitrile 9 either with sodium methylate in methanol followed by addition of ammonium chloride or by reaction with lithium hexamethyldisilazane followed by addidion of hydrochloric acid in /-propanol.
  • the 2-substituted malonic esters 12 were prepared according to published procedures [3] by reacting dimethylchloromalonate 11 with the appropriate alcohol 13 in acetone and potassium carbonate as base. The compounds 12 were dissolved in methanol and sodium methylate was added and stirring was continued for about 30 min followed by the addition of an amidine derivative 10. Stirring at ambient temperature was continued for another 8 h.
  • the pyrimidine derivatives 18 are the central intermediates which can be transformed to the the derivatives 20 by reaction with a di-hydroxy-compound represented by Formula 19 in the presence of a base such as sodium hydride in a solvent like THF at rt to 90°C.
  • the derivatives 20 are then transformed to compounds of the general Formula I by reacting them with a carbamoylating agent as oulined above.
  • the aqueous layer was extracted with 400 ml of DCM.
  • the combined DCM layers were dried over Na 2 SO and the solvent 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 1 b 5.28 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1 b) was added to a solution of 3.37 g of sodium methylate in 30 ml of methanol and the resulting solution was stirred at rt for 30 min. Then 3.91 g of pyrazine-2-carboxamidine was added and stirring was continued for 20 h. The solvent was removed in vacuo, and the residue was dissolved in water. The solution was acidified by adding citric acid.

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Abstract

L'invention concerne de nouvelles sulfonylamino-pyrimidines, ainsi que leur utilisation en tant que principes actifs dans la préparation de compositions pharmaceutiques. L'invention concerne également d'autres aspects, notamment des procédés de préparation de ces composés, des compositions pharmaceutiques contenant au moins un de ces composés et en particulier leur utilisation en tant qu'antagonistes du récepteur de l'endothéline.
PCT/EP2002/003947 2001-04-11 2002-04-09 Nouvelles sulfonylamino-pyrimidines WO2002083650A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104892528A (zh) * 2014-12-10 2015-09-09 上海工程技术大学 一种2-硫代巴比妥酸衍生物的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US7858632B2 (en) 2004-03-05 2010-12-28 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
US9556127B2 (en) 2004-03-05 2017-01-31 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
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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
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