AU3536701A - Butyne diol derivatives - Google Patents

Butyne diol derivatives Download PDF

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AU3536701A
AU3536701A AU35367/01A AU3536701A AU3536701A AU 3536701 A AU3536701 A AU 3536701A AU 35367/01 A AU35367/01 A AU 35367/01A AU 3536701 A AU3536701 A AU 3536701A AU 3536701 A AU3536701 A AU 3536701A
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hydroxy
lower alkyl
substituted
phenyl
alkyl
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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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    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • C07D401/04—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
    • 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
    • C07D403/14—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 three or more hetero rings

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

WO 01/46156 PCT/EPOO/12743 Butyne Diol Derivatives 5 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 10 compositions containing one or more compounds of the general formula I and especially their use as endothelin receptor antagonists. Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411. 15 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) 20 46:328). Two endothelin receptors have been cloned and characterized in mammals (ETA, ETB) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732). The ETA receptor is characterized by higher affinity for ET-1 25 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). In contrast, 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 30 (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 WO 01/46156 PCT/EPOO/12743 -2 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 ETB receptors are highly similar in structure and belong to the superfamily of G-protein 5 coupled receptors. 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 10 heart failure, renal failure, migraine and asthma. As a consequence, 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 15 systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction. Today, no endothelin receptor antagonist is marketed yet, several are in clinical trials. However, these molecules possess a number of weaknesses 20 such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics or safety problems (e.g. liver enzyme increases). Furthermore, the contribution of differential ETA / ETB receptor blockade to the clinical outcome is not known. Thus, tailoring of the physicochemical, pharmacokinetic properties and the selectivity profile of each antagonist for a 25 given clinical indication is mandatory. We have discovered a new class of butyne-diol derivatives of the structure below and found that they allow the specific tailoring described above. The inhibitory activity of the compounds of formula I on endothelin receptors 30 can be demonstrated using the test procedures described hereinafter: WO 01/46156 PCT/EPOO/12743 -3 5 For the evaluation of the potency and efficacy of the compounds of the general formula I the following tests were used: 1) Inhibition of endothelin binding to membranes from CHO cells 10 carrying human ET receptors: For competition binding studies, 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 et al, FEBS Lett 1993; 334:210). 15 The assay was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, including 25 mM MnCl 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 200C with 8 pM [ 125 l]ET-1 (4000 cpm) and increasing concentrations of unlabelled 20 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. ZOrich, Switzerland). To each well, 50 uL of scintillation cocktail was added (MicroScint 20, Canberra Packard S.A. Zorich, Switzerland) and 25 the filter plates counted in a microplate counter (TopCount, Canberra Packard S.A. ZOrich, Switzerland). All the test compounds were dissolved, diluted and added in DMSO. The assay was run in the presence of 2.5% DMSO which was found not to 30 interfere significantly with the binding. IC50 was calculated as the concentration of antagonist inhibiting 50 % of the specific binding of ET-1. For reference compounds, the following IC50 values were found: ETA cells: 0.075 WO 01/46156 PCT/EPOO/12743 -4 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ETB cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3. The IC50 values obtained with compounds of formula I are given in Table 1 WO 01/46156 PCT/EPOO/12743 -5 Table 1: Compound of
IC
50 [nM] ETA ETB Example 1g 26 77 Example 2c 126 44 Example 3e 22 1520 Example 4d 53 2030 Example 5b 38 635 Example 9d 16 49 Example I1d 49 97 Example 18 79 36 Example 19 112 45 Example 21 230 44 Example 58 7 123 Example 70 94 375 Example 71 13 28 Example 72 1 42 Example 81 1 197 Example 84 2 241 Example 89 13 1140 Example 94 13 107 5 2) Inhibition of endothelin-induced contractions on isolated rat aortic rings (ETA receptors) and rat tracheal rings (ETB receptors): 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 WO 01/46156 PCT/EPOO/12743 -6 tracheal (ETB receptors). Adult Wistar rats were anesthetized and exsanguinated. The thoracic aorta or trachea were excised, dissected and cut in 3-5 mm rings. The endothelium/epithelium was removed by gentle rubbing of the intimal surface. Each ring was suspended in a 10 ml isolated organ 5 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, CaCl 2 2.5, glucose 10) kept at 37 0 C and gassed with 95% 02 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 10 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 5 o is the 15 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 pA 2 values obtained with compounds of formula I are given in Table 2. 20 Table 2: pA 2 Compound of aortic rings trachea Example 4d 7.15 5.89 Example 9d 7.11 6.47 Example I1d 7.05 7.03 Example 19 <5 7.62 Example 58 7.57 WO 01/46156 PCT/EPOO/12743 -7 Example 59 7.70 Example 72 7.70 Example 81 7.56 Example 84 8.11 Because of their ability to inhibit the endothelin binding, the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to 5 endothelin. Examples of such 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. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent 10 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 15 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; 20 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. 25 Preferred applications are intravenous, intra-muscular, eye drops or oral administrations. The dosage used depends upon the type of the specific WO 01/46156 PCT/EPOO/12743 -8 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, 5 could contain a number of binding agents, filling excipients, carrier substances or diluents. 10 The present invention relates to butyne diol derivatives of the general formula I, 0 0 R NH N
R
3 general formula I R N 0
OR
2 wherein 15 R' 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 20 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 halogen, lower WO 01/46156 PCT/EPOO/12743 -9 alkyl, lower alkoxy, hydroxy-lower alkyl, halogen, trifluoromethyl; 2-pyridyl; 5 substituted 2-pyridyl substituted with lower alkyl, lower alkoxy; benzyl; mono-, di- or tri-substituted benzyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower 5 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, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen 10 atoms; aryl; heteroaryl;
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, 15 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 20 nitrogen, sulfur or oxygen atoms which may be mono-or di-substituted with halogen, lower alkyl, lower alkoxy; benzyl; mono-, di- or tri-substituted benzyl 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 25 phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; 2-pyrimidyl; mono- or di-substituted 2-pyrimidyl substituted with lower alkyl, lower alkoxy, hydroxy-lower alkyl, halogen, trifluoromethyl, five membered heteroaryl rings containing one or two 30 nitrogen, sulfur or oxygen atoms; aryl; heteroaryl; heterocyclyl; a group of the formula -C(A)-B-Ra, wherein WO 01/46156 PCT/EPOO/12743 -10 A represents 0 or S; B represents NH or a bond; and 5 Ra 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 10 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 15 halogen, lower alkyl, lower alkoxy, trifluoromehtyl, trifluoromethoxy; six membered heteroaryl rings containing one or two nitrogen atoms which may be mono-, di- or tri-substituted with halogen, lower alkyl, lower akyloxy, trifluoromethyl; 20 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; heteroary; mono- or 25 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, 30 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- WO 01/46156 PCT/EPOO/12743 - 11 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 5 alkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; aryl; aryl-amino; arylthio; aryloxy; aryl-lower alkyl; heteroaryl; heterocyclyl; X represents oxygen; sulfur; NH or a bond; 10 and pure enantiomers, enantiamerically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and pharmaceutically acceptable salts thereof. In the definitions of the general formula I - if not otherwise stated - the 15 expression 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 20 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 25 acetylenyl, 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 6 carbon atoms , e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl which may be substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower 30 alkoxy-lower alkyl and lower alkenylen groups. The expression heterocyclyl means saturated or unsaturated ( but not aromatic ) five-, six- or seven membered rings containing one or two nitrogen, oxygen or sulfur atoms which WO 01/46156 PCT/EPOO/12743 - 12 may be the same or different and which rings may be substituted with lower alkyl, amino, halogen, nitro, hydroxy, lower alkoxy, e.g. piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahyd rofu ranyl, dihydropyrrolyl, dihydroimidazolyl, 5 dihydropyrazolyl, pyrazolidinyl etc. and substituted derivatives of such rings with substituents as outlined above. The expression 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 10 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 membred aromatic rings containing a sulfur, nitrogen or oxygen atom and benzo fused derivatives thereof, five- membered aromatic rings containing two nitrogen 15 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. furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, pyridazinyl, oxazolyl, etc. whereby such rings may be substituted with lower alkyl, amino, amino-lower alkyl, 20 halogen, hydroxy, lower alkoxy or trifluoromethyl. The expression 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 25 alkylendioxy. The expression pharmaceutically acceptable 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, 30 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 WO 01/46156 PCT/EPOO/12743 -13 acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc. The compounds of the general formula I might have one or more asymmetric 5 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, 10 crystallization etc. Because of their ability to inhibit the endothelin binding, 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 15 increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such 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. They can also be used for 20 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, 25 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. These compositions may be administered in enteral or oral form e.g. as 30 tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectically in form of suppositories. These compounds WO 01/46156 PCT/EPOO/12743 -14 may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions. These pharmaceutical compositions may contain the compounds of formula 1 5 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. 10 For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used. For the preparation of 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, 15 fatty acids (fats ), liquid or half-liquid polyols etc. The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts 20 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. a- and p-blockers like Phentolamine, Phenoxybenzamine, Atenolol, Propranolol, Timolol, 25 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, 30 Acetolamide, Bumetanide, Furosemide, Metolazone, Chlortalidone etc.; Sympatholitics like Methyldopa, Clonidine, Guanabenz, Reserpine etc.; and WO 01/46156 PCT/EPOO/12743 -15 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 5 situation. In general the dosage given in oral form should daily be between about 3 mg and about 3 g, preferably between about 10 mg and about I 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 inl to 3 doses per day which are of equal weight. As usual children should receive lower 10 doses which are adapted to body weight and age. A preferred group of compounds are compounds of formula I wherein R', R 2 , and R 4 are as defined above, and wherein 15
R
3 represents phenyl; mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, trifluoromethoxy, halogen; X represents oxygen or a single bond, 20 and pharmaceutically acceptable salts thereof. Another preferred group of compounds are compounds of formula I WO 01/46156 PCT/EPOO/12743 -16 0 0 N S NH R 5 N R 3 formula LI R N 0 O R 2 wherein R 2 , R 3 , R 4 , and X are as defined in formula I above, and R 5 represents lower alkyl, 5 and pharmaceutically acceptable salts of compounds of formula 11. Another group of preferred compounds are compounds of formula Ill 0 0 R NH N R3 formula III N 0 O N R6 N R7
R
8 10 wherein R', R 3 , R 4 , and X are as defined in formula I above, WO 01/46156 PCT/EPOO/12743 -17 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; 5 and pharmaceutically acceptable salts thereof. Yet another group of preferred compounds are compounds of formula IV 00 R NH x N R formula IV R N O H O N Ra 0 10 wherein R 1 , R 3 , R 4 , Ra and X are as defined in formula I above, and pharmaceutically acceptable salts thereof. 15 Another group of preferred compounds are compounds of formula I wherein
R
1 , R 3 , R 4 , and X are as defined in formula I above, and wherein R 2 represents lower alkyl, and pharmaceutically acceptable salts thereof. 20 WO 01/46156 PCT/EPOO/12743 - 18 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. 5 The compounds of the general formula I are prepared from compounds of the formula V by one of the two pathways given below. The compounds VI are reacted either with a compound R 2 -Y, where Y represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfate, etc., or, in the case where R 2 represents a group of the formula C(A)-NH-Ra, with a compound 10 Ra-N=C=A where R' and A are as defined in the general formula 1. Compounds of the formula Vil 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. 15 Chem. Soc. Jpn. 28 (1955), 80-82; J. Org. Chem. 18 (1953), 1601-1606). 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 20 507; J. Org. Chem. 63 (1998), 4291-4298).
WO 01/46156 PCT/EPOO/12743 -19 s '-, NH OH R NH R NH OHR N R 3 NR
R
4 N 0 R4 N cl VI v v V I OH OR 2 00 O R1 ~NH HO VII x N R R4 N o I
OR
2 Compounds V are prepared from the corresponding dichloro compounds VIII (Bioorg. Med. Chem. Letters 7 (1997), 2223-2228, Chimia 50 (1996), 519 5 524, and references cited therein). CI N R 4" R N CI
VIII
WO 01/46156 PCT/EPOO/12743 - 20 Treatment of VIII with an excess of the appropiate sulfonamide potassium salt in the presence or absence of a base (e.g. triethylamine, Honig's base) in a solvent (e.g DMF, DMSO) at room temperature furnished the desired compounds V. The sulfonamide potassiums salts may be prepared according 5 to e.g. Bioorg. Med. Chem. Letters 7 (1997), 2223-2228. Compounds VIll 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 POCl 3 , PC 5 , or mixtures thereof, etc. each in the 10 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. 1959, 741-742). 15 0 N 0 H Ix In a standard method as described by Pinner (for review see e.g. The Pyrimidines, by D.J. Brown, Wiley Interscience, New York 1970), the 20 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).
WO 01/46156 PCT/EPOO/12743 -21 OMe, OEt OH NH O " R 3 ,N X R 3 R NH 4 2 0 OMe,OEt R N OH X XI Ix The amidines X were prepared form the corresponding nitriles XII by 5 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). 10 R4,- C N XII The malonic ester derivatives XI were either commercially available or were prepared following the procedures found in the literature (e.g. J. Am. Chem. 15 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). 20 As the case may be, 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, WO 01/46156 PCT/EPOO/12743 - 22 synthesised compounds of formula I were converted into a pharmaceutically acceptable salt in a manner known per se.
WO 01/46156 PCT/EPOO/12743 - 23 Examples The following examples illustrate the invention but do not at all limit the scope thereof. All temperatures are stated in 0C. 5 The compounds given below were prepared according to the procedure described above. All compounds were characterized by 1 H-NMR (300MHz) and occasionally by 13 C-NMR (75MHz) (Varian Oxford, 300MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d 10 = doublet, t = triplet; m = multiplet), by LC-MS (Waters Micromass; ZMD platform with ESI-probe with Alliance 2790 HT; Column: 2x3Omm, Gromsil ODS4, 3pim, 120A; Gradient: 0 - 100% acetonitrile in water, 6 min, with 0.05% formic acid, flow: 0.45ml/min; tr is given in min, molecular mass of the fraction at tr), by TLC (TLC-plates from Merck, silica gel 60 F 254 ) and 15 occasionally by melting point. Abbreviations: 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. 20 Example 1 a) To a solution of 0.23 g sodium in 40 ml methanol was added 10.62 g 4 cyanopyridine at room temperature. Stirring was continued for 6 h followed by 25 the addition of 5.9 g ammoniumchloride and stirring was continued for another 10 h. Then 120 ml diethylether was added and the precipitate was filtered off after 30 min and washed once with 20 ml of diethylether. The product was dried under high vacuum. 14.95 g 4-amidino-pyridine hydrochloride was obtained as a white powder. 30 b) 48 ml 2-methoxy-phenol (guajacol) were slowly added to a stirred suspension of 70.8 g potassium carbonate in 480 ml acetone followed by WO 01/46156 PCT/EPOO/12743 -24 heating to 45 0 C. Then 63.2 ml dimethylchloromalonate in 50 ml acetone were added within 20 min. The reaction mixture was heated to reflux for 16 h. The solvent was evaporated under reduced pressure, the residue taken into water and extracted with DCM. The combined organic layers were dried over 5 sodium sulfate and evaporated. The oily product was crystallized from methyl tert.-butyl-ether. 86 g dimethyl-(o-methoxyphenoxy)malonate was obtained. c) To a stirred solution of 9.7 g sodium methylate in 100 ml methanol a solution of 21.7 g dimethyl-(o-methoxyphenoxy)malonate in 50 ml methanol 10 was added within 15 min and stirring was continued for 30 min followed by the addition of 15.0 g 4-amidino-pyridine hydrochloride followed by stirring at room temperature for 20 h. The reaction mixture was concentrated in vacuo. The solid residue was stirred with ether. The obtained powder was filtered off and dissolved in 300 ml water. Acetic acid was added to pH = 4. The 15 precipitated product was filtered off, washed with water and dried in vacuo at 50'C. 20.1 g 5-(o-methoxyphenoxy)-4,6-d ihyd roxy-2-(4-pyridyl)-pyrimid ine (is possibly also present as the tautomeric 5-(o-methoxyphenoxy)-2-(4-pyridyl) tetrahydropyrimidine-4,6-dion) was obtained as a white powder. 20 d) 10 g of the 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-pyrimidine, 11.2 g N-ethyldiisopropylamine, 11 g tetraethylammoniumchloride and 13.8 g phosphorous pentachloride were dissolved in 25 ml phosphorous oxychloride and heated to reflux for 3 h. The mixture was evaporated in vacuo, toluene was added and the mixture was again evaporated. The residue was taken 25 into DCM and poured onto ice/water. The layers were separated, the organic layer was washed with water, dried over sodium sulfate and evaporated. After recrystallization from acetone, 6.52 g of 4,6-dichloro-5-(o-methoxyphenoxy) 2-(4-pyridyl)-pyrimidine was obtained. 30 e) 5-isopropyl pyridine-2-sulfonamide potassium salt was prepared according to procedures disclosed in EP 0713875 Al and Bioorganic & Medicinal Chemistry Letters, 7 (1997), 2223-2228.
WO 01/46156 PCT/EPOO/12743 - 25 f) I 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 5 became clear within a few h. After 16 h at room temperature, most of the solvent was removed by evaporation under reduced pressure. The residue was taken up in 20 ml water and the pH was adjusted to 4-5 by adding about 1 ml of acetic acid. A precipitate formed. The precipitate was filtered off, washed with water and dried. The yellow powder was further purified by 10 column chromatography on silica gel eluting first with hexane: ethyl acetate 1:1 then with DCM : MeOH 10 : 1. 1.43 g of 5-isopropyl-N-[6-chloro-5-(o methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a slightly yellow powder. LC-MS: tR = 5.00 min, [M+1]* = 512.19, [M-1]- = 510.26. 15 g) At 0-5'C, 5.04 g of 2-butyne-1,4-diol was added portionwise to a stirred slurry of 0.7 g sodium hydride in 30 ml of dry DMF and 5 ml of DMPU. Stirring was continued until the evolution of gas had ceased. To the resulting suspension 1.5 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4 20 pyridyl)-4-pyrimid inyl]-2-pyridine sulfonamide was added at room temperature and the mixture was stirred at 950C for 24 h. Eventually, the slurry was allowed to cool to room temperature, was then poured onto 100 ml of an aqueous solution of 10% citric acid and extracted twice with 150 ml of ethyl acetate. The combined organic layers were washed twice with 50 ml of water, 25 dried over MgSO 4 and evaporated. The remaining dark brown oil was purified by column chromatography on 80 g of silica gel eluting with DCM containing 0-5% of methanol. This gave 0.82 g of 5-isopropyl-N-[6-(4-hydroxy-2 butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyri mid inyl]-2-pyrid ine sulfonamide as a pale yellow solid. LC-MS: tR = 4.39min, [M+1]* = 562.29, [M 30 l]- = 560.41.
WO 01/46156 PCT/EPOO/12743 - 26 Example 2 a) A solution of 15.2 g of 4-tert.-butylbenzene sulfonyl chloride in 150 ml of THF was cooled with an ice bath. 15.2 ml of 25% aqueous ammonium 5 hydroxide solution was added dropwise. After the addition was completed, the solution was stirred at room temperature for 15 min. The solvent was removed in vacuo. The residue was again dissolved in ethyl acetate and washed twice with water. The organic phase was dried over Na 2
SO
4 , evaporated and dried. The resulting 14.8 g of a white powder was dissolved 10 in 75 ml of methanol and 7.5 g of potassium tert. butylate was added. The solution was briefly stirred at room temperature and evaporated. The resulting residue was carefully dried to give 16.3 g of 4-tert.-butylbenzene sulfonamide potassium salt as a white solid. 15 b) To a solution of 6.1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl) pyrimidine (Example 1, Section a) to d)) in 100 ml of dry DMF 8.8 g of 4-tert.
butyl benzene sulfonamide potassium salt was added at room temperature. The solution was stirred over night at room temperature. The solution was added to a mixture of 150 ml of water and 100 ml of diethyl ether. The pH was 20 adjusted to 5 by adding acetic acid. The precipitate that formed was collected, washed with water and diethyl ether. The resulting powder was suspended in boiling ethyl acetate. The mixture was allowed to cool in an icebath. Eventually, the solid material was collected and dried to yield 6.6 g of 4-tert.
butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid inyl]-benzene 25 sulfonamide as beige crystals. LC-MS: tR = 5.80 min, [M+1]* = 525.31, [M-1]~ = 523.48 c) At room temperature, 6.9 g of 2-butyne-1,4-diol was added portionwise to a stirred slurry of 0.96 g sodium hydride in 25 ml of dry DMF and 5 ml of dry 30 DMPU. Stirring was continued until the evolution of gas had ceased. To the resulting suspension 2.1 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy) 2-(4-pyridyl)-4-pyrimid inyl]-benzene sulfonamide was added at room WO 01/46156 PCT/EPOO/12743 - 27 temperature and the mixture was stirred at 90 0 C for 48 h. Eventually, the solvent was removed under reduced pressure and the resulting oil was treated with 150 ml of 10% aqueous acetic acid. The dark solution was extracted with 150 ml of DCM. The organic layer was washed with water, 5 dried over MgSO 4 and evaporated. The resulting dark brown oil was further purified by column chromatography on silica gel eluting with toluene : ethyl acetate 4:1 to 1:4. This furnished 1.28 g of 4-tert.-butyl-N-[6-(4-hydroxy-2 butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide as a beige foam. LC-MS: tR = 4.87 min, [M+1]* = 575.32, [M-1]- = 10 573.45. Example 3 a) To a suspension of 70 g of 2-bromo-5-methyl pyridine in 500 ml of water 15 200 ml 25% aqueous hydrochloric acid was added at room temperature. To the clear solution 68 g of thiourea was added and the mixture was heated to reflux. After 4 h another 34 g and after 18 h further 17 g of thiourea was added. After 24 h the solution was cooled with an icebath and 360 ml of 4 N sodium hydroxide solution was added. A precipitate formed which dissolved 20 upon adding 600 ml of DCM. The organic layer was separated and washed with 500 ml of water. The aqueous phase was acidified to pH 3 using hydrochloric acid and repeatedly extracted with DCM. The combined organic layers were dried over MgSO 4 , evaporated and dried under reduced pressure. This gave 46.9 g of a yellow solid which was recrystallised from 25 boiling ethanol to furnish 37.6 g of 5-methyl-2-thio-pyridine in form of pale yellow platelets which sinter at 1680C and gradually melt between 179 and 1900C. 'H-NMR(CDC1 3 , 300 MHz): 2.17 (s, 3H); 7.24(dd, J=2.0, 8.8, 1H); 7.41(t, J=1.0, 1H); 7.47(d, J=8.8, 1H); 14.03(s br, 1H). 30 b) To a mixture of 100 ml of 25 % aqueous hydrochloric acid and 250 ml of DCM was added 18 g of 5-methyl-2-thio-pyridine. While the mixture was vigorously stirred and kept at -100C 250 ml of an aqueous solution containing WO 01/46156 PCT/EPOO/12743 - 28 13% of sodium hypochlorite was carefully added. Upon completion of the addition, stirring was continued for 10 min. The organic layer was separated. To the aqueous layer 250 ml of DCM was added and the mixture was again treated as before with a further 250 ml batch of bleach. Upon completion of 5 the addition, the organic layer was separated. The aqueous layer was extracted five times with 200 ml DCM. The organic layers were combined, dried over MgSO 4 and evaporated. The resulting oil was dissolved in 125 ml of THF and cooled to -20'C. 25 ml of saturated aqueous ammonium hydroxide solution was slowly added. The mixture was stirred over night at 10 room temperature. Excess of ammonia was neutralised by adding hydrochloric acid and the THF was removed in vacuo. The remaining aqueous solution was extracted three times with 150 ml of ethyl acetate. The combined organic layers were dried over MgSO 4 and the solvent was evaporated. The remaining solid was recrystallised from boiling ethyl acetate 15 to yield 13.35 g of 5-methyl-2-pyridine sulfonamide in form of beige crystals.
'H-NMR(D
6 -DMSO, 300 MHz): 2.37(s, 3H); 7.36(s, 2H); 7.78-7.85(m, 2H); 8.53(s, IH); LC-MS: tR = 2.32 min, [M+1]* = 173.04, [M-1]- = 171.10. c) To a solution of 18.54 g of 5-methyl-2-pyridine sulfonamide in 400 ml of 20 methanol was added 12.08 g of potassium tert.-butylate. The solution was stirred at room temperature for 5 min. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give 22.64 g of 5-methyl-2-pyridine sulfonamide potassium salt as a beige solid. 25 d) Under argon 4 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl) pyrimidine (Example 1, section a) to d)) was dissolved in 40 ml of dry DMF and 3.62 g of 5-methylpyridine-2-sulfonamide potassium salt followed by 2.95 ml of HOnig's base was added. The dark solution was stirred at room temperature for 22 h. A further portion of 0.75 g of 5-methylpyridine-2 30 sulfonamide potassium salt was added and stirring was continued for 18 h. The reaction mixture was poured onto 150 ml of 10% citric acid in water and extracted four times with 150 ml of ethyl acetate. The combined organic WO 01/46156 PCT/EPOO/12743 - 29 phase was washed with water, dried over MgSO 4 , and evaporated. The resulting residue was suspended in 20 ml of methanol and 20 ml of acetone. The precipitate was collected, washed with methanoi:diethyl ether 1:1 and dried. This furnished 4.56 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2 5 (4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: tR = 4.38 min, [M+1]* = 484.58, [M-1]~ = 482.51. e) At room temperature, 8.0 g of 2-butyne-1,4-diol was added portionwise to a stirred slurry of 0.99 g sodium hydride in 25 ml of dry DMF and 5 ml of dry 10 DMPU. Stirring was continued until the evolution of gas had ceased. To the resulting suspension 2.0 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy) 2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide was added at room temperature and the mixture was stirred at 900C for 16 h. Eventually, the slurry was allowed to cool to room temperature, was then poured onto a 15 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 20 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. This gave 1.65 g of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyri mid inyl]-2 pyridine sulfonamide as a beige powder. LC-MS: tR = 3.81 min, [M+1]* = 25 534.63, [M-1]~ = 532.54. Example 4 a) 4,6-d ihyd roxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimid ine [or its 30 tautomer 5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-tetrahydropyrimidine-4,6 dion] was prepared as disclosed in EP 0 526 708 Al from 2-amidino pyrimidine and dimethyl-(o-methoxyphenoxy)malonate.
WO 01/46156 PCT/EPOO/12743 -30 b) 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine was pre pared as disclosed in EP 0 526 708 Al from 4,6-dihydroxy-5-(o methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (which may also be present in 5 the tautomeric form 5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-tetrahydro pyrimidine-4,6-dione). c) A solution of 3.5 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl) pyrimidine and 4.98 g of 5-isopropyl-2-pyridine sulfonamide potassium salt 10 (Example 1, section e) in 40 ml of DMSO was stirred at room temperature for 4 h. The mixture was poured onto water and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate that formed was collected, washed with water and diethyl ether and dried to furnish 5.1 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2 15 pyrimidinyl)-4-pyrimi-dinyl]-2-pyridine sulfonamide as a white solid. LC-MS: tR = 4.87 min, [M+1]* = 513.32, [M-1]- = 511.26. d) 273 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained 20 as a beige foam starting from 600 mg of 5-isopropyl-N-[6-chloro-5-(o methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyrid ne sulfonamide following the procedure given in Example 1g. LC-MS: tR = 4.31 min, [M+1]* = 563.71, [M-1]- = 561.59. 25 Example 5 a) 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimi dinyl]benzene sulfonamide was prepared as disclosed in EP 0 526 708 Al from 4,6-d ichloro-5-(o-methoxyphenoxy)-2-(2-pyrimid inyl)-pyrimidine and p 30 tert.-butyl benzene sulfonamide potassium salt. LC-MS: tR = 5.50 min, [M+1]* = 526.29, [M-1]- = 524.43.
WO 01/46156 PCT/EPOO/12743 -31 b) 295 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was obtained as a beige foam starting from 1.4 g of 4-tert.-butyl-N-[6-chloro-5-(o methoxyphenoxy)-2-(2-pyrimid inyl)-4-pyrimid inyl]benzene sulfonamide 5 following the procedure given in Example 1g. LC-MS: tR = 5.06 min, [M+1]* = 576.33, [M-1]~ = 574.45. Example 6 10 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 in 15 water a white precipitate formed. The precipitate was collected, washed with water and ethyl acetate, and dried. This furnished 2.67 g of 5-methyl-N-[6 chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyrid ine sulfonamide as a white powder. LC-MS: tR = 4.23 min, [M+1]* = 485.56, [M-1] = 483.48. 20 b) 347 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy) 2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a pale yellow foam starting from 1 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy) 2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide following the procedure 25 given in Example I g. LC-MS: tR = 3.90 min, [M+1]* = 535.66, [M-I]- = 533.55. Example 7 a) A solution of 10 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1 b) 30 in 80 ml dry methanol was cooled to OC. 6.71 g of sodium methylate was added portionenwise. To the suspension was added 2.84 g of acetamidine hydrochloride and the mixture was stirred overnight at room temperature. The WO 01/46156 PCT/EPOO/12743 - 32 solvent was removed under reduced pressure and the residue was suspended in 100 ml of diethyl ether. The solid was filtered off, washed with another portion of 100 ml of diethyl ether and dissolved in 50 ml of water. The pH was adjusted to 4 by adding 25 ml of glacial acetic acid. The white 5 precipitate that formed was filtered off, washed with water and dried to yield 5.17 g of 5-(o-methoxyphenoxy)-4,6-dihyd roxy-2-methyl-pyrimidine (or a tautomer) as a white powder. b) A solution of 10.9 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl 10 pyrimidine (or a tautomer) in 150 ml of POCl3 was stirred at 50*C for 72 h. The excess of POC13 was evaporated, toluene was added to coevaporate traces of POCl 3 . Eventually, an ice:water mixture was carefully added to the residue and the pH was adjusted to 8 using 3 N sodium hydroxide solution. The mixture was further diluted with 300 ml of water and extracted with 500 15 ml of DCM. The organic layer was separated, washed with 300 ml of water, dried over Na 2
SO
4 and evaporated. The residue was dissolved again in DCM and filtered through a pad of silica gel eluting with DCM. The solvent was removed in vacuo. The resulting residue was dried to furnish 8.7 g of 4,6 d ichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine as a beige powder. 20 c) To a solution of 2.15 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl pyrimidine in 40 ml of DMSO was added 3.59 g of 5-isopropyl-2-pyridine sulfonamide potassium salt. The mixture was stirred for 72 h at room temperature. The solution was diluted with 350 ml of water and extracted 25 twice with 200 ml of diehtyl ether. The organic layers were extracted twice with water. The combined aqueous layers were acidified to pH 4 with 5 ml of acetic acid and extracted twice with DCM. The organic layers were washed with water, and dried over Na 2
SO
4 . The solution was treated with activated charcoal, filtered over Celite and evaporated. The residue was suspended in 30 30 ml of diethyl ether, filtered off and dried to give 3.15 g of 5-isopropyl-N-[6 chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimid inyl]-2-pyridine sulfonamide WO 01/46156 PCT/EPOO/12743 - 33 as a pale beige powder. LC-MS: tR = 5.18 min, [M+1]* = 449.25, [M-1]- = 447.31. d) 440 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o 5 methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyrid ine sulfonamide was obtained as a beige foam starting from 600 mg of 5-isopropyl-N-[6-chloro-5 (o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyrid ine sulfonamide following the procedure given in Example 1g, but stirring the reaction mixture for 48 h at 950C. LC-MS: tR = 4.74 min, [M+1]* = 499.25, [M-1]- = 497.33 10 Example 8 a) At room temperature 2.95 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 3c) was added to a suspension of 2 g of 4,6-dichloro-5-(o 15 methoxyphenoxy)-2-methyl-pyrimidine (Example 7b) in 30 ml DMSO. The mixture was stirred at room temperature for 48 h and was then poured onto 300 ml of water. The aqueous solution was extracted twice with 200 ml of diethyl ether. The organic layers were extracted with water and the aqueous layers were combined and acidified with 3 ml of acetic acid to pH 4. 20 Precipitation of the product was enhanced by adding 100 ml of saturated aqueous sodium chloride and cooling the mixture to OC. Eventually, the precipitate was filtered off, washed with cold water and dried under high vacuum to give 2.26 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2 methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: tR 25 4.79 min, [M+1]* = 421.42, [M-1]- = 419.46. b) 584 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy) 2-methyl-4-pyrimid inyl]-2-pyridine sulfonamide was obtained as a beige powder starting from 950 mg of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy) 30 2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide following the procedure given in Example 1g, but stirring the reaction mixture for 72 h at 95*C. LC-MS: tR = 4.32 min, [M+1I] = 471.57, [M-1]- = 469.40.
WO 01/46156 PCT/EPOO/12743 - 34 Example 9 a) A solution of 32.75 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1 5 b) in 250 ml of methanol was cooled to O'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 addedand stirring was continued for 72 h. The solvent of the beige suspension was evaporated and the residue was washed twice with 10 150 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 precipitate was collected, washed with water and dried under high vacuum to yield 17.01 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N morpholino)-pyrimidine (or a tautomer) as a slightly beige powder. 15 b) At 0 C 50 ml of POCl 3 was carefully added to 27.5 ml of HOnig's base. To this mixture 17 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino) pyrimidine was added portionwise. The resulting mixture was stirred over night at 1300C. The excess of reagents was evaporated and traces of POCl 3 20 were removed by coevaporation with toluene. The black residue was treated with 50 ml of DCM and 50 ml of a water:ice mixture. After stirring for 15 min, the mixture was diluted with 400 ml of water and 400 ml of DCM. The organic layer was separated and washed with 300 ml of water. The aqueous layer was extracted with 400 ml of DCM. The combined DCM layers were dried 25 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 30 crystalline powder.
WO 01/46156 PCT/EPOO/12743 - 35 c) To a suspension of 4 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(N morpholino)-pyrimidine in 60 ml of DMSO was added 5.32 g of 5-isopropyl-2 pyridine sulfonamide potassium salt (Example 3c) and 0.98 ml of HOnig's base. The mixture was stirred at 650C for 72 h. The dark solution was poured 5 onto 500 ml of water and quickly filtered through celite. The filtrate was extracted with 500 ml and 250 ml of diethyl ether. The organic layers were extracted with 100 ml of water. The aqueous layers were combined, acidified with 3.5 ml of acetic acid and cooled to O'C. The precipitate that formed was collected, washed with cold water and dried under high vacuum to furnish 10 4.94 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N-morpholino)-4 pyrimidinyl]-2-pyridine sulfonamide as a brownish powder. LC-MS: tR = 5.46 min, [M+1]* = 520.22, [M-1]~ = 518.36. d) At 0-5'C 3.97 g of 2-butyne-1,4-diol was added portionwise to a stirred 15 slurry of 0.55 g sodium hydride in 30 ml of dry DMF and 7 ml of DMPU. Stirring was continued until the evolution of gas had ceased. To the resulting suspension 1.2 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(N morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide was added at room temperature and the mixture was stirred at 950C for 6 days. Eventually, the 20 slurry was allowed to cool to room temperature, was then poured onto 100 ml of an aqueous solution of 10% citric acid and extracted twice with 150 ml of ethyl acetate. The combined organic layers were washed twice with 75 ml of water, dried over MgSO 4 and evaporated. The remaining brown oil was purified by column chromatography on 120 g of silica gel eluting with DCM 25 containing 0-2% of methanol. Fractions containing the desired compound were combined, evaporated and the residue was further purified by recrystallisation from diethyl ether: hexane. This gave 327 mg of 5-isopropyl N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4 pyrimidinyl]-2-pyridine sulfonamide as colourless crystals with a melting point 30 of 196.0-197.5'C. LC-MS: tR = 4.89 min, [M+1]* = 570.30, [M-1]- = 568.43. Furthermore, 494 mg of the starting material was recovered as a beige foam.
WO 01/46156 PCT/EPOO/12743 - 36 Example 10 a) At 50C 12.7 g of sodium methylate was added portionwise to a solution of 18.9 g of dimethyl-(o-methoxyphenoxy)malonate (Example 1 b) in 450 ml of 5 methanol. Upon completion of the addition stirring was continued at room temperature for 30 min followed by the addition of 6 g of formamidine hydrochloride. The mixture was stirred at room temperature for 72 h. Eventually, the solvent was removed under reduced pressure and the remaining residue was suspended in diethyl ether. The solid material was 10 filtered off and dissolved in 100 ml of water. The solution was acidified with conc. hydrochloric acid. A white precipitate formed. The precipitate was collected, washed with water and dried to give 15.1 g of 5-(o methoxyphenoxy)-4,6-dihydroxy-pyrimidine (or a tautomer) as a white powder. 15 b) To a solution of 7.5 g of 5-(o-methoxyphenoxy)-4,6-dihydroxy-pyrimidine in 90 ml of POCl 3 24 ml of N,N-dimethylaniline was added. The mixture was heated to 1600C and stirred for 2.5 h. Excess of POCl 3 was distilled off under reduced pressure. Traces of POCl 3 were coevaporated with toluene. The 20 remaining oil was treated with a water:ice mixture. The mixture was acidified with I N hydrochloric acid and extracted twice with diethyl ether. The combined organic layers were washed twice with dilute aqueous hydrochloric acid, dried over MgSO 4 and evaporated. The remaining solid was washed with methanol and dried. This gave 4.75 g of 4,6-dichloro-5-(o 25 methoxyphenoxy)-pyrimidine as a pale yellow powder. c) To a solution of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine in 40 ml of DMSO 3.7 g of 4-tert.butylbenzene sulfonamide potassium salt was added. The resulting solution was stirred for 20 h at room temperature. 30 Eventually, the mixture was poured onto 400 ml of water and washed twice with 200 ml of diethyl ether. The organic layers were extracted with 200 ml of water. The combinded aqueous layers were acidified with conc. hydrochloric WO 01/46156 PCT/EPOO/12743 - 37 acid. The mixture was cooled to OC and 100 ml of brine was added. The precipitate that formed was collected and dried to yield 2.7 g of 4-tert.-butyl-N [6-chloro-5-(o-methoxyphenoxy)-4-pyrimid inyl]-benzene sulfonamide as a white powder. LC-MS: tR = 5.80 min, [M+1]* = 448.17, [M-1]- = 446.21. 5 d) To a slurry of 0.79 g of sodium hydride in 45 ml of DMF and 15 ml of DMPU 5.68 g of 2-butyne-1,4-diol was added at 100C. The mixture was stirred until no more gas evolved. Then 1.48 g of 4-tert.-butyl-N-[6-chloro-5 (o-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide was added and the 10 mixture was stirred at 900C for 72 h. The solvent was removed in vacuo and the residue was taken up in 150 ml of 10% aqueous acetic acid. The mixture was extracted three times with 150 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The resulting brown oil was purified by column chromatography on silica gel 15 eluting with hexane:ethyl acetate 3:1 to 1:1. This furnished 320 mg of 4-tert.
butyl-N-[6-(4-hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl] benzene sulfonamide as a slightly brown foam. LC-MS: tR = 5.21 min, [M+1]* = 498.35, [M-1]~ = 496.49. 20 Example 11 a) A solution of 6.8 g of sodium methylate in 200 ml of methanol was cooled to OC. A solution of 10.3 g of diethyl 2-(p-tolyl)-malonate in 50 ml of methanol was slowly added. Upon completion of the addition the solution was allowed 25 to come to room temperature and 7.57 g of 4-amidino-pyridine hydrochloride (Example 1a) was added. The mixture was stirred at room temperature for 16 h. Eventually, the solvent was removed under reduced pressure and the remaining residue was dissolved in 2 M hydrochloric acid. The solution was extracted with diethyl ether, then adjusted to pH 5 with 10 M sodium 30 hydroxide solution. A precipitate formed. The precipitate was collected, washed with cold water and dried at 600C under high vacuum. This gave 8.77 WO 01/46156 PCT/EPOO/12743 - 38 g of 4,6-dihydroxy-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (or a tautomer) as orange crystals. b) To a mixture of 8.0 g of 5-(p-tolyl)-4,6-dihydroxy-pyrimidine and 100 ml of 5 POCl 3 25 ml of diethylamine was added at room temperature. The mixture was stirred for 16 h at 60*C. The excess of POC 3 was distilled off under reduced pressure. The remaining oil was dissolved in 300 ml of DCM and treated with 300 ml of water. The aqueous layer was separated and extracted three times with DCM. The combined organic layers were washed with water 10 and brine, dried over MgSO 4 and evaporated. The resulting residue was suspended in isopropanol. The solid material was collected, washed with isopropanol, and diethyl ether and dried to give 7.2 g of 4,6-dichloro-2-(4 pyridyl)-5-(p-tolyl)-pyrimidine as a white crystalline powder. 15 c) A mixture of 654 mg of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine and 1051 mg of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1e) in 20 ml of DMF was stirred for 16 h at room temperature. Eventually, the solvent was distilled off under reduced pressure and the resulting residue was treated with 100 ml of 10% aqueous acetic acid and 100 ml of DCM. The 20 layers were separated. The aqueous layer was extracted two more times with DCM. The combined organic layers were washed once with water, dried over MgSO 4 and evaporated. The remaining residue was crystallised from isopropanol:diethyl ether. The yellow crystals were collected, washed with cold isopropanol and diethyl ether, and dried under high vacuum to furnish 25 870 mg of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimid inyl]-2 pyridine sulfonamide. LC-MS: tR = 5.06 min, [M+1I] = 480.40, [M-1]~ = 478.48. d) To a slurry of 0.34 g of sodium hydride in 15 ml of DMF and 4 ml of DMPU 2.4 g of 2-butyne-1,4-diol was added at room temperature. The mixture was 30 stirred until no more gas evolved. Then 0.67 g of 5-isopropyl-N-[6-chloro-5-(p tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyrid ine sulfonamide was added and the mixture was stirred at 900C for 48 h. The solvent was removed in vacuo and WO 01/46156 PCT/EPOO/12743 - 39 the residue was taken up in 100 ml of 10% aqueous acetic acid. The mixture was extracted three times with 100 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The resulting brown oil was purified by column chromatography on silica gel 5 eluting with DCM containing 4-10% of methanol. This furnished a fraction which after recrystallisation from DCM : ethyl acetate gave 43 mg of 5 isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl] 2-pyridine sulfonamide as pale yellow crystals. A second fraction gave 456 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4 10 pyrimidinyl]-2-pyridine sulfonamide with about 90% purity as a brown oil. LC MS: tR = 4.53 min, [M+1]* = 530.23, [M-1]- = 528.21. Example 12 15 a) At 00C a solution of 14.2 g of diethyl 2-(p-tolyl)-malonate in 50 ml of methanol was slowly added to a solution of 9.4 g of sodium methylate in 300 ml of methanol. Upon completion of the addition the reaction mixture was allowed to warm up and 5.4 g of formamidine hydrochloride was added. The mixture was stirred at room temperature for 16 h. The solvent was removed 20 under reduced pressure and the remaining residue was treated with 150 ml of 2 N hydrochloric acid. The suspension was stirred for 0.5 h. At 0-5*C, the pH was carefully adjusted to 4 using 10 N sodium hydroxide solution. The precipitate was collected, washed with cold water, isopropanol, and diethyl ether and dried under high vacuum at 650C to give 11.2 g of 4,6-dihydroxy-5 25 (p-tolyl)-pyrimidine (or a tautomer) as a white powder. b) At room temperature 10 ml of N,N-dimethylaniline was added to a mixture of 5.1 g of 4,6-dihydroxy-5-(p-tolyl)-pyrimidine and 75 ml of POCl 3 . The reaction mixture was stirred at 700C for 16 h. The excess of POCl 3 was 30 distilled off and the remaining oil was treated with a ice:water mixture and extracted three times with diethyl ether. The combined organic layers were washed with IN aqueous hydrochloric acid followed by brine, dried over WO 01/46156 PCT/EPOO/12743 -40 MgSO 4 and evaporated. The remaining brown oil was crystallised from isopropanol. The pale yellow crystals were collected, washed with cold isopropanol and dried under high vacuum to furnish 4.1 g of 4,6-dichloro-5-(p tolyl)-pyrimidine. 5 c) A mixture of 0.8 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine and 1.68 g of 4-tert.
butylbenzene sulfonamide potassium salt (Example 2a) in 20 ml of DMSO was stirred at room temperature for 24 h. The mixture was poured onto 200 ml of water and extracted twice with 100 ml of diethyl ether. The organic 10 layers were extracted twice with 50 ml of water. The combined aqueous layers were acidified hydrochloric acid. The resulting fine suspension was extracted twice with ethyl acetate. The combined organic layers were dried over Na 2
SO
4 and evaporated. The residue was dried under high vacuum to give 1.34 g 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene 15 sulfonamide as a white powder. LC-MS: tR = 5.92 min, [M+1]* = 416.20, [M-1]~ = 414.24. d) 700 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4 pyrimidinyl]-benzene sulfonamide was obtained as a brown glass starting 20 from 1.45 g of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide following the procedure given in Example 10d. LC-MS: tR = 5.38 min, [M+1]* = 466.24, [M-1]- = 464.32. Example 13 25 a) A solution of 2.71 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine (Example 10b) and 5.0 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example le) in 50 ml of DMF was stirred at room temperature for 20 h. The solvent was removed in vacuo, the residue was taken up in 200 ml of 10% 30 aqueous acetic acid and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The crude product was crysallised from a mixture of WO 01/46156 PCT/EPOO/12743 -41 2-propanol and diethyl ether. The crystals were collected, washed with cold 2 propanol and diethyl ether and dried to give 2.8 g of 5-isopropyl-N-[6-chloro 5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as white crystals. LC-MS: tR = 4.99 min, [M+1]* = 435.25, [M-1]- = 433.28. 5 b) To a solution of 11.02 g of 2-butyne-1,4-diol in 100 ml of DMF and 30 ml of DMPU was added 2.8 g sodium hydride in portions. After completion of the addition stirring was continued for 1.5 h followed by the addition of 2.78 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine 10 sulfonamide. The mixture was heated to 90'C and stirred for 65 h. The solvent was removed in vacuo, the residue was taken up in 250 ml of 10% aqueous citric acid and extracted twice with 250 ml of ethyl acetate. The organic phase was washed with water and brine, dried over MgSO 4 and evaporated. Column chromatography of the crude product on silica gel eluting 15 with hexane:ethyl acetate 1:1 to 1:4 furnished 1.27 g of 5-isopropyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-4-pyri mid i nyl]-2-pyrid ine sulfonamide as a brown solid. Beige crystals were obtained for analytical purposes after crystallisation of a part of the isolated product from 2-propanol. LC-MS: tR = 4.50 min, [M+1]+ = 485.27, [M-1]- = 483.41. 20 Example 14 a) A solution of 15.2 g of 4-tert.-butylbenzene sulfonyl chloride in 150 ml of THF was cooled with an ice bath. 15.2 ml of 25% aqueous ammonium 25 hydroxide solution was added dropwise. After the addition was completed, the solution was stirred at r.t. for 15 min. The solvent was removed in vacuo. The residue was again dissolved in ethyl acetate and washed twice with water. The organic phase was dried over Na 2
SO
4 , evaporated and dried. The resulting 14.8 g of a white powder was dissolved in 75 ml of methanol and 7.5 30 g of potassium tert. butylate was added. The solution was briefly stirred at r.t. and evaporated. The resulting residue was carefully dried to give 16.3 g of 4 tert.-butylbenzene sulfonamide potassium salt as a white solid.
WO 01/46156 PCT/EPOO/12743 -42 b) A solution of 2.0 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(N-morpholino) pyrimidine (Example 9b) and 2.96 g of 4-tert.-butylbenzene sulfonamide potassium salt in 30 ml of DMSO was stirred at r.t. for 24 h. After 1 g of 4 5 tert.-butylbenzene sulfonamide potassium salt had been added, stirring was continued for another 24 h at r.t. followed by 16 h at 550C. Eventually, the mixture was poured into 350 ml of water and 350 ml of ether. The mixture was acidified by adding acetic acid. A white, sticky precipitate formed. The mixture was stirred at 00C for 1 h. The precipitate was filtered off, washed 10 with water and ether and dissolved again in ethyl acetate. The solvent was removed in vacuo and the remaining solid was suspended in 100 ml of diethyl ether. The solid was filtered off, washed with additional diethyl ether and dried to give 2.57 g of 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin 4-yl-pyrimidin-4-yl]-benzene sulfonamide as a white powder. LC-MS: tR = 5.98 15 min, [M+1]* = 533.29, [M-1]~ = 531.41. c) To a suspension of 675 mg of NaH in 45 ml of DMF and 5 ml of DMPU was added 4.85 g of 2-butyne-1,4-diol. The mixture was stirred at room temperature until evolution of gas had ceased. Then 1.5 g of 4-tert.-butyl-N 20 [6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide was added and the resulting mixture was heated to 950C and stirred for 5 days. Eventually, the mixture was pourred into 150 ml of 10% aqueous citric acid and extracted three times with 150 ml of ethyl acetate. The organic layers were washed with water and brine, dried over MgSO 4 and 25 evaporated. The resulting residue was purified by column chromatography on silicagel eluting with hexane:ethyl acetate 1:1 to give 265 mg of 4-tert.-butyl N-[6-(4-hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl pyrimidin-4-yl]-benzene sulfonamide as a beige foam along with 1.13 g of the starting material 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-morpholin 30 4-yl-pyrimidin-4-yl]-benzene sulfonamide. LC-MS: tR = 5.39 min, [M+1]* = 583.41, [M-1]- = 581.35.
WO 01/46156 PCT/EPOO/12743 -43 Example 15 a) To a suspension of 4 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(N morpholino)-pyrimidine (Example 9b) in 20 ml of DMSO was added 4.72 g of 5 5-methyl-2-pyridine sulfonamide potassium salt (Example 3c). The mixture was stirred at 550C for 17 h. The dark solution was poured into 500 ml of water and quickly filtered through celite. The filtrate was extracted with 500 ml and 250 ml of diethyl ether. The organic layers were extracted with 100 ml of water. The aqueous layers were combined, acidified with 3.5 ml of acetic acid 10 and cooled to OC. The precipitate that formed was collected, washed with cold water and dried under high vacuum to furnish 4.42 g of 5-methyl-N-[6 chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide as a brownish powder..LC-MS: tR = 4.80 min, [M+1]* = 492.31, [M-1]~ = 490.37. 15 b) To a suspension of 712 mg of NaH in 30 ml of DMF and 7 ml of DMPU was added 5.11 g of 2-butyne-1,4-diol. The mixture was stirred at room temperature until evolution of gas had ceased. Then 1.45 g of 5-methyl-N-[6 chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine 20 sulfonamide was added and the resulting mixture was heated to 950C and stirred for 4 days. Eventually, the mixture was pourred into 200 ml of 10% aqueous citric acid and extracted three times with 200 ml of ethyl acetate. The organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The resulting residue was purified by column chromatography on 25 silicagel eluting with a gradient of hexane:ethyl acetate 1:1 to ethyl acetate to give 470 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(2 methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder along with 660 mg g of the starting material 5-methyl-N-[6 chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine 30 sulfonamide. LC-MS: tR = 4.33 min, [M+1]* = 542.35, [M-1]- = 540.32. Example 16 WO 01/46156 PCT/EPOO/12743 -44 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-sulfonamide potassium salt (Example le) in 100 ml of DMF was stirred at room temperature for 72 h. The solvent was 5 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 100C. The precipitate that formed was collected, washed with water and diethtyl ether and dried under high vaccum at 50'C. This furnished 7.67 g 10 of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-4-pyrimid inyl]-2-pyridine sulfonamide as a white powder. LC-MS: tR = 5.13 min, [M+1]* = 403.24, [M-1]- = 401.28. b) To a solution of 21.5 g of 2-butyne-1,4-diol in 200 ml of DMF and 50 ml of DMPU was added in portions 5.5 g of NaH 55% in mineral oil. After the 15 evolution of gas had ceased 5.04 g of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-4 pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was stirred for 80 h at 90'C. The solvent was removed in vacuo and the residue was partitioned between 300 ml of 10% aqueous citric acid and 300 ml of ethyl acetate. The aqueous phase was extracte two more times with ethyl 20 acetate. The combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate from 1:1 to 1:4 to give 2.0 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4 pyrimidinyl]-2-pyridine sulfonamide as a brown solid. LC-MS: tR = 4.64 min, 25 [M+1]* = 453.28, [M-1]- = 451.40. Example 17 To a suspension of 14 mg of a 55% sodium hydride dispersion in mineral oil 30 in 2 ml of dry DMF and 2 ml of dry THF 80 mg of 5-isopropyl-N-[6-(4-hydroxy 2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl)-2-pyridine sul-fonamide (Example 1g) was added. After stirring for 10 min, 41 mg of 2- WO 01/46156 PCT/EPOO/12743 -45 chloro-pyrimidine was added. Stirring was continued for 1 h at 700C. The reaction mixture was poured onto 50 ml of 10% aqueous citric acid. The solution was extracted twice with 50 ml of ethyl acetate. The combined organic layers were twice washed with water, dried over MgSO 4 and 5 evaporated. The remaining residue was purified by column chromagraphy on silica gel eluting with a gradient of 0-2% of methanol in DCM. This furnished 72 mg of 5-isopropyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy phenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a colourless foam. LC-MS: tR = 4.74 min, [M+1]* = 640.35, [M-1]- = 638.49. 10 Example 18 88 mg of 5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy) 5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid inyl]-2-pyridine sulfonamide was 15 obtained as a pale yellow solid starting from 80 mg of 5-isopropyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyri mid inyl)-2 pyridine sulfonamide (Example 1g) and 78 mg of 4,6-dimethoxy-2-methyl sulfonylpyrimidine following the procedure given in Example 17. LC-MS: tR 5.34 min, [M+I]* = 700.42, [M-1]~ = 698.52. 20 Example 19 To a suspension of 76 mg of a 55% sodium hydride dispersion in mineral oil in 15 ml of dry THF 403 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5 25 (o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide (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 30 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 4 and evaporated. The remaining residue was purified WO 01/46156 PCT/EPOO/12743 -46 by column chromagraphy on silica gel eluting with a gradient of 5-10% of methanol in DCM. This furnished 256 mg of 4-tert.-butyl-N-[6-(4-(2 pyri mid inyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidi nyl]-benzene sulfonamide as a colourless foam. LC-MS: tR = 5.21 min, [M+I1] 5 = 653.69, [M-1]~ = 651.78. Example 20 200 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o 10 methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide was obtained in the form of beige crystals starting from 196 mg of 4-tert.-butyl-N [6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidi nyl]-benzene sulfonamide (Example 2c) and 73 mg of 5-bromo-2 chloropyrimidine following the procedure given in Example 19. However, the 15 crude product was purified by crystallisation from a methanol isopropanol mixture. LC-MS: tR = 5.63 min, [M+1]* = 731.65, [M-1]- = 729.66. Example 21 20 A suspension of 400 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide (Example 2c), 116 mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine and 147 mg of potassium carbonate in 15 ml of DMF was stirred at 90'C for 16 h. Further 42 mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine was added and stirring was 25 continued at 90'C for 24 h. Eventually, the solvent was removed in vacuo, and the resulting residue partitioned between 50 ml of 5% aqueous acetic acid and 50 ml of DCM. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of DCM. The combined organic layers were washed with water, dried over MgSO 4 and evaporated. 30 The remaining oil was purified by column chromatography on silica gel eluting with toluene : ethyl acetate 4:1 to 1:1. The product obtained was recrystallised from ethyl acetate : diethyl ether to give 76 mg of 4-tert.-butyl-N-[6-(4-(4,6- WO 01/46156 PCT/EPOO/12743 -47 d imethoxy-2-pyri mid i nyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4 pyridyl)-4-pyrimidinyl]-benzene sulfonamide as white crystals. LC-MS: tR 5.84 min, [M+1]* = 713.35, [M-1]- = 711.45. 5 Example 22 To a suspension of 41 mg of a 55% sodium hydride dispersion in mineral oil in 5 ml of dry DMF and 5 ml of dry THF 200 mg of 5-methyl-N-[6-(4-hydroxy 2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine 10 sulfonamide (Example 3e) was added. After strirring for 10 min, 47 mg of 2 chloropyrimidine was added. Stirring was continued for 20 h at room temperature. Then another 20 mg of 2-chloropyrimidine was added and stirring was continued for another 24 h. Eventually, the reaction mixture was poured onto 50 ml of 10% aqueous citric acid. The solution was extracted 15 twice with 50 ml of ethyl acetate. The combined organic layers were twice washed with water, dried over MgSO 4 and evaporated. The remaining residue was purified by column chromagraphy on silica gel eluting with a gradient of 0-3% of methanol in DCM. This furnished 147 mg of 5-methyl-N-[6-(4-(2 pyri mid i nyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid i 20 nyl]-2-pyridine sulfonamide as a pale yellow powder. LC-MS: tR 4.26 min, [M+1]* = 612.29, [M-1]~ = 610.43. Example 23 25 65 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimid inyloxy)-2-butynyloxy)-5-(o methoxyphenoxy)-2-(4-pyridy)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a pale yellow solid starting from 100 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid inyl]-2 pyridine sulfonamide (Example 3e) and 44 mg of 5-bromo-2-chloropyrimidine 30 following the procedure given in Example 22. LC-MS: tR = 4.77 min, [M+1]* = 690.22, [M-1]- = 688.36.
WO 01/46156 PCT/EPOO/12743 -48 Example 24 91 mg of 5-methyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5 (o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was 5 obtained as a pale yellow solid starting from 100 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyri mid inyl]-2 pyridine sulfonamide (Example 3e) and 82 mg of 4,6-dimethoxy-2 methylsulfonylpyrimidine following the procedure given in Example 22. LC MS: tR = 4.80 min, [M+1]* = 672.32, [M-1]- = 670.46. 10 Example 25 72 mg of 5-methyl-N-[6-(4-(4,6-dimethyl-2-pyrimidinyloxy)-2-butynyloxy)-5-(o methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyrid ine sulfonamide was 15 obtained as a pale yellow solid starting from 80 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyri mid inyl]-2 pyridine sulfonamide (Example 3e) and 70 mg of 4,6-dimethyl-2 methylsulfonylpyrimidine following the procedure given in Example 22. LC MS: tR = 4.68 min, [M+1]* = 640.32, [M-1]~ = 638.39. 20 Example 26 59 mg of 5-isopropyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained 25 as a beige foam starting from 80 mg of 5-isopropyl-N-[6-(4-hydroxy-2 butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyri mid i nyl)-4-pyri mid i nyl]-2-pyrid i ne sulfonamide (Example 4d) and 33 mg of 2-chloropyrimidine following the procedure given in Example 22. LC-MS: tR = 4.55 min, [M+1]* = 641.63, [M-1] 639.47. 30 Example 27 WO 01/46156 PCT/EPOO/12743 -49 78 mg of 5-isopropyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyrid ine 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-pyri mid inyl)-4-pyri mid inyl]-2 5 pyridine sulfonamide (Example 4d) and 55 mg of 5-bromo-2-chloropyrimidine following the procedure given in Example 22. LC-MS: tR = 4.99 min, [M+1]* = 719.56, [M-1]- = 717.28. Example 28 10 65 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-benzene sulfonamide was obtained as a beige foam starting from 75 mg of 4-tert.-butyl-N-[6-(4-hydroxy 2-butynyloxy)-5-(o-methoxyph enoxy)-2-(2-pyri mid i-nyl)-4-pyri mid i nyl] 15 benzene sulfonamide (Example 5b) and 103 mg of 5-bromo-2 chloropyrimidine following the procedure given in Example 22. LC-MS: tR 5.83 min, [M+1I] = 732.31, [M-1]- = 730.36. Example 29 20 71 mg of 4-tert.-butyl-N-[6-(4-(4,6-d imethoxy-2-pyrimid inyloxy)-2-butynyloxy) 5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-benzene sulfonamide was obtained as a colourless foam starting from 75 mg of 4-tert.-butyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimi-dinyl)-4 25 pyrimidinyl]-benzene sulfonamide (Example 5b) and 140 mg of 4,6 dimethoxy-2-methylsulfonylpyrimidine following the procedure given in Example 22. LC-MS: tR = 5.92 min, [M+1]* = 714.42, [M-1]- = 712.50. Example 30 30 20 mg of 5-methyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained WO 01/46156 PCT/EPOO/12743 - 50 as a colourless foam starting from 60 mg of 5-methyl-N-[6-(4-hydroxy-2 butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 6b) and 36 mg of 2-chloropyrimidine following the procedure given in Example 22. LC-MS: tR = 4.37 min, [M+1]* = 613.29, [M-1] 5 = 611.45. Example 31 75 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o 10 methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a colourless powder starting from 80 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] 2-pyridine sulfonamide (Example 6b) and 120 mg of 5-bromo-2 chloropyrimidine following the procedure given in Example 22. LC-MS: tR = 15 4.64 min, [M+1]* = 691.64, [M-1]- = 689.45. Example 32 84 mg of 5-methyl-N-[6-(4-(4,6-d imethoxy-2-pyrimid inyloxy)-2-butynyloxy)-5 20 (o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a colourless powder starting from 80 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] 2-pyridine sulfonamide (Example 6b) and 65 mg of 4,6-dimethoxy-2 methylsulfonylpyrimidine following the procedure given in Example 22. LC 25 MS: tR = 4.72 min, [M+1]* = 673.70, [M-1]- = 671.53. Example 33 73 mg of 5-isopropyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy 30 phenoxy)-2-methyl-4-pyrimid inyl]-2-pyrid ine sulfonamide was obtained as a colourless foam starting from 80 mg of 5-isopropyl-N-[6-(4-hydroxy-2 butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfon- WO 01/46156 PCT/EPOO/12743 - 51 amide (Example 7d) and 46 mg of 2-chloropyrimidine following the procedure given in Example 17. LC-MS: tR = 5.18 min, [M+1]* = 577.27, [M-1]~ = 575.36. Example 34 5 75 mg of 5-isopropyl-N-[6-(4-(4,6-d imethoxy-2-pyrimid inyloxy)-2-butynyloxy) 5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a colourless foam starting from 80 mg of 5-isopropyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2 10 pyridine sulfonamide (Example 7d) and 88 mg of 4,6-dimethoxy-2 methylsulfonylpyrimidine following the procedure given in Example 17. LC MS: tR = 5.80 min, [M+1]* = 637.31, [M-1]- = 635.40. Example 35 15 76 mg of 5-isopropyl-N-[6-(4-(4,6-dimethyl-2-pyrimidinyloxy)-2-butynyloxy)-5 (o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyrid ine sulfonamide was obtained as a colourless foam starting from 80 mg of 5-isopropyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyri mid inyl]-2-pyri 20 dine sulfonamide (Example 7d) and 75 mg of 4,6-dimethyl-2 methylsulfonylpyrimidine following the procedure given in Example 17. LC MS: tR = 5.51 min, [M+1]* = 605.35, [M-1]~ = 603.43. Example 36 25 98 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o methoxy-phenoxy)-2-methyl-4-pyrimid inyl]-2-pyridine sulfonamide was obtained as a colourless foam starting from 80 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidi nyl]-2-pyri 30 dine sulfonamide (Example 8b) and 96 mg of 5-bromo-2-chloropyrimidine following the procedure given in Example 22. LC-MS: tR = 5.33 min, [M+1]= 627.20, [M-1]- = 625.27.
WO 01/46156 PCT/EPOO/12743 - 52 Example 37 80 mg of 5-methyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidi nyloxy)-2-butynyloxy)-5 5 (o-methoxy-phenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a colourless foam starting from 80 mg of 5-methyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyri dine sulfonamide (Example 8b) and 74 mg of 4,6-dimethoxy-2 methylsulfonylpyrimidine following the procedure given in Example 22. LC 10 MS: tR = 5.46 min, [M+1]* = 609.31, [M-1]~ = 607.38. Example 38 80 mg of 5-methyl-N-[6-(4-(4,6-dimethyl-2-pyrimid inyloxy)-2-butynyloxy)-5-(o 15 methoxy-phenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a colourless foam starting from 80 mg of 5-methyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyri dine sulfonamide (Example 8b) and 79 mg of 4,6-dimethyl-2 methylsulfonylpyrimidine following the procedure given in Example 22. LC 20 MS: tR = 5.10 min, [M+1]* = 577.30, [M-1]~ = 575.41. Example 39 To a suspension of 58 mg of a 55% sodium hydride dispersion in mineral oil 25 in 15 ml of dry THF 280 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5 (p-tolyl)-4-pyrimidinyl]-benzene sulfonamide (Example 12) was added. After stirring for 1 h, 144 mg of 4,6-dimethoxy-2-methylsufonyyrimidine was added. Stirring was continued for 12 h at reflux. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% 30 aqueous citric 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 WO 01/46156 PCT/EPOO/12743 - 53 brine, dried over MgSO 4 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. This furnished 91 mg of 4-tert.-butyl-N-[6-(4-(4,6 5 dimethoxy-2-pyrimid inyloxy)-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a colourless foam. LC-MS: tR = 6.32 min, [M+1]* = 604.31, [M 1] = 602.43. Example 40 10 To a suspension of 88 mg of a 55% sodium hydride dispersion in mineral oil in 15 ml of dry THF 375 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5 (p-tolyl)-4-pyrimidinyl]-benzene sulfonamide (Example 12) was added. After stirring for 1 h, 170 mg of 5-bromo-2-chloropyrimidine was added. Stirring 15 was continued for 60 h at 400C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous citric 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 20 MgSO 4 and evaporated. The crude product was crystallised from 2-propanol containing a small amount of diethyl ether to give 168 mg of 4-tert.-butyl-N-[6 (4-(5-bromo-2-pyrimid inyloxy)-butynyloxy)-5-(p-tolyl)-4-pyrimid inyl]-benzene sulfonamide as beige crystals. LC-MS: tR 6.22 min, [M+1]* = 624.28. 25 Example 41 To a suspension of 29 mg of a 55% sodium hydride dispersion in mineral oil in 15 ml of dry THF 150 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5 (o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide (Example 10) was 30 added. After stirring for 0.5 h, 64 mg of 5-bromo-2-chloropyrimidine was added. Stirring was continued for 40 h at 400C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% WO 01/46156 PCT/EPOO/12743 - 54 aqueous citric 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 4 and evaporated. The crude product was crystallised 5 from 2-propanol to give 126 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2 pyrimid inyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimid inyl]-benzene sulfonamide as beige crystals. LC-MS: tR = 6.07 min, [M+1]* = 656.24, [M-1]* = 654.34. 10 Example 42 126 mg of 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2 butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimid inyl]-benzene sulfonamide was obtained as a colourless foam starting from 150 mg of 4-tert.-butyl-N-[6-(4 15 hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide (Example 10) and 72 mg of 4,6-dimethoxy-2 methylsulfonylpyrimidine following the procedure given in Example 41. LC MS: tR = 6.13 min, [M+1]* = 635.81, [M-1]- = 633.77. 20 Example 43 To a suspension of 243 mg of K2CO3 in 15 ml of DMF 450 mg of 5-isopropyl N-[6-(4-hyd roxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimid inyl]-2-pyrid ine sulfonamide (Example 11) was added. After stirring for 0.5 h at 90'C, 192 mg 25 of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added and stirring was continued for 16 h at 900C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous acetic acid and 50 ml of DCM. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of DCM. The combined organic 30 layers were washed with water and brine, dried over MgSO 4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with DCM:methanol 20:1 to give 88 mg of 5-isopropyl-N-[6-(4-(4,6- WO 01/46156 PCT/EPOO/12743 - 55 dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4 pyrimidinyl]-2-pyridine sulfonamide as a beige foam. LC-MS: tR = 5.54 min, [M+1]* = 668.38, [M-1]* = 666.39. 5 Example 44 186 mg of 5-isopropyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as beige crystals starting from 250 mg of 5-isopropyl-N-[6-(4-hydroxy-2 10 butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 13) and 194 mg of 5-bromo-2-chloropyrimidine following the procedure given in Example 41. LC-MS: tR = 5.43 min, [M+1]* = 643.18, [M-1] = 641.29. 15 Example 45 To a solution of 250 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 13) in 15 ml of THF was added 48 mg of NaH. The mixture was stirred for 2 h at room 20 temperature before 120 mg of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added. Stirring was continued for 16 h at reflux. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous citric 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 25 ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The crude product was purified by chromatography on prep. tIc-plates coated with silica gel with ethyl acetate:methanol: sat. aqueous ammonia 8:2:1 to give 71 mg of 5-isopropyl N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(o 30 methoxyphenoxy)-4-pyrimidinyl]-2-pyrid ine sulfonamide as a beige foam. LC MS: tR = 5.50 min, [M+1]* = 623.29, [M-1]* = 621.40.
WO 01/46156 PCT/EPOO/12743 - 56 Example 46 To a suspension of 9 mg of NaH 55% dispersion in mineral oil in 4 ml of DMF:THF 1:1 was added 50 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2 5 butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimid in-4-yl]-benzene sulfonamide (Example 14). After the evolution of gas had ceased, 42 mg of 5 bromo-2-chloropyrimidine was added and the mixture was stirred for I h at 650C before it was diluted with 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated, washed with 50 ml of water, 10 dried over MgSO 4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 3:2 to give 60 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimid inyloxy)-2-butynyloxy)-5-(2 methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a colourless foam. MS: tR = 6.14min, [M+1]* = 739.18, [M-1]* = 741.32. 15 Example 47 48 mg of 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy) 5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimid in-4-yl]-benzene sulfonamide 20 was obtained as a colourless foam starting from 50 mg of 4-tert.-butyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4 yl]-benzene sulfonamide (Example 14) and 47 mg of 4,6-dimethoxy-2 methylsulfonylpyrimidine following the procedure given in Example 46. LC MS: tR = 6.21 min, [M+1]* = 721.44, [M-1]* = 719.35 25 Example 48 37 mg of 5-methyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(2 methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide was 30 obtained as a beige powder starting from 50 mg of 5-methyl-N-[6-(4-hydroxy 2-butynyloxy)-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2 pyridine sulfonamide (Example 15) and 45 mg of 5-bromo-2-chloropyrimidine WO 01/46156 PCT/EPOO/12743 - 57 following the procedure given in Example 46. LC-MS: tR = 5.31 min, [M+1]* = 700.34, [M-1]+ = 698.24. Example 49 5 48 mg of 5-methyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5 (2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimid inyl]-2-pyrid ine sulfonamide was obtained as a colourless solid starting from 50 mg of 5-methyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(N-morpholino)-4 10 pyrimidinyl]-2-pyridine sulfonamide (Example 15) and 50 mg of 4,6 dimethoxy-2-methylsulfonylpyrimidine following the procedure given in Example 46. LC-MS: tR = 5.42 min, [M+1]* = 680.43, [M-1]* = 678.36. Example 50 15 128 mg of 5-isopropyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(p tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a beige foam starting from 230 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-toly) 4-pyrimidinyl]-2-pyridine sulfonamide (Example 16) and 194 mg of 5-bromo-2 20 chloropyrimidine following the procedure given in Example 45. LC-MS: tR = 5.49 min, [M+1]* = 611.25, [M-1]* = 609.39. Example 51 25 68 mg of 5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy) 5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a beige foam starting from 230 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-toly) 4-pyrimidinyl]-2-pyridine sulfonamide (Example 16) and 120 mg of 4,6 dimethoxy-2-methylsulfonylpyrimidine following the procedure given in 30 Example 45. LC-MS: tR = 5.60 min, [M+1]* = 591.21, [M-1]* = 589.24.
WO 01/46156 PCT/EPOO/12743 - 58 Example 52 To a solution of 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyrid ine sulfonamide 5 (Example 1g) and 10 mg of 4-dimethylaminopyridine in 5 ml of dry chloroform 25 ptl of n-butyl isocyanate was added at room temperature. The mixture was heated to 650C and stirred for 42 h. After 6 h, 18 h, and 28 h another portion of 25 pl of n-butyl isocyanate was added. Eventually, the mixture was diluted with 50 ml of ethyl acetate. The solution was washed twice with 20 ml of 10 water. The aqueous layers were extracted once with ethyl acetate. The combined organic layers were dried over MgSO 4 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. This gave 39 mg of n-butyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2 15 sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2 ynyl ester as a pale yellow foam. LC-MS: tR = 5.17 min, [M+1]* = 661.37, [M I]- = 659.51. Example 53 20 To a solution of 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1g) and 10 mg of 4-dimethylaminopyridine in 5 ml of dry chloroform 25 pl of phenyl isocyanate was added at room temperature. The mixture was 25 heated to 650C 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 4 and evaporated. The residue was purified by column chromatography on silica gel eluting first with hexane : 30 ethyl acetate 1:1 then with DCM containing 4% of methanol. This gave 40 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2 methoxy-phenoxy)-2-pyridin-4-y-pyrimidin-4-yloxy]-but-2-yny ester as an off- WO 01/46156 PCT/EPOO/12743 - 59 white solid which melts at 163-164"C. LC-MS: tR = 5.15 min, [M+1]* = 681.36, [M-1]~ = 679.51. Example 54 5 39 mg of m-tolyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5 (2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-yny ester was obtained as an off-white solid starting from 50 mg of 5-isopropyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid i nyl]-2 10 pyridine sulfonamide (Example 1g) and 25 [LI of m-tolyl isocyanate following the procedure given in Example 53. Melting point: 163-165 0 C. LC-MS: tR = 5.33 min, [M+1]* = 695.39, [M-1]- = 693.53. Example 55 15 45 mg of (4-methoxyphenyl)-carbamic acid 4-[6-(5-isopropyl-pyridine-2 sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2 ynyl ester was obtained as a pale yellow foam starting from 50 mg of 5 isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl) 20 4-pyrimidinyl]-2-pyridine sulfonamide (Example Ig) and 25 [LI of 4 methoxyphenyl isocyanate following the procedure given in Example 53. LC MS: tR = 5.06 min, [M+1]* = 711.35, [M-1]- = 709.48. Example 56 25 27 mg of (2-methoxy-phenyl)-carbamic acid 4-[6-(5-isopropyl-pyridine-2 su lfonylamino)-5-(2-methoxy-phenoxy)-2-pyrid in-4-yl-pyrimidin-4-yloxy]-but-2 ynyl ester was obtained as a pale yellow foam starting from 50 mg of 5 isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl) 30 4-pyrimidinyl]-2-pyridine sulfonamide (Example Ig) and 25 l of 2 methoxyphenyl isocyanate following the procedure given in Example 53. LC MS: tR = 5.30 min, [M+1]* = 711.36, [M-1]- = 709.49.
WO 01/46156 PCT/EPOO/12743 - 60 Example 57 36 mg of (2-fluorophenyl)-carbamic acid 4-[6-(5-isopropyl-pyridine-2 5 sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2 ynyl ester was obtained as a white solid starting from 50 mg of 5-isopropyl-N [6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4 pyrimidinyl]-2-pyridine sulfonamide (Example 1g) and 12 mg of 2-fluorophenyl isocyanate following the procedure given in Example 53. LC-MS: tR 5.16 10 min, [M+1]* = 699.36, [M-1] = 697.28. Example 58 A solution of 50 mg of 2-picolinic acid azide (prepared from 2-picolinic acid 15 according to Chem. Pharm. Bull. 25 (1977) 1651-1657) and 10 mg of DMAP in 8 ml of chloroform was stirred for I h at 750C. 50 mg of 5-isopropyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid inyl]-2 pyridine sulfonamide (Example 1g) followed by 3 ml of DMF was added and the resulting clear solution was stirred for 16 h at 750C. The mixture was 20 diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid followed by 50 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep. tic-plates with dichlormethane:methanol 10:1 to give 41 mg of 2-pyridinyl-carbamic acid 4 [6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4 25 yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a white solid. LC-MS: tR = 4.74 min, [M+1]* = 682.47, [M-1]~ = 680.41. Example 59 30 271 mg of 2-pyrazinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2 sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyrid in-4-yl-pyrimid in-4-yloxy]-but-2 ynyl ester was obtained as a white powder starting from 300 mg of 5- WO 01/46156 PCT/EPOO/12743 - 61 isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl) 4-pyrimidinyl]-2-pyridine sulfonamide (Example Ig) and 199 mg of pyrazine-2 carbonyl azide (prepared from pyrazin-2-carboxylic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example 5 58. LC-MS: tR = 4.73 min, [M+1]* = 683.44, [M-1]- = 681.37. Example 60 Under argon, a suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2 10 butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid inyl]-2-pyrid ine sulfonamide (Example 3), 10 mg of DMAP and 25 l of cyclohexylisocyanate in 4 ml of chloroform and 3 ml of DMF was stirred for 72 h at 700C. The mixture was diluted with 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and 2x25 mlf of water. The organic phase was dried over 15 MgSO 4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with a gradient of hexane:ethyl acetate 1:1 to ethyl acetate, then with DCM containing 4% of methanol to give 38 mg of cyclohexylcarbamic acid 4-[6-(5-methylpyridine-2-sulfonylamino)-5-(2 methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a 20 beige foam. LC-MS: tR = 4.89 min, [M+1]* = 659.33, [M-1]- = 657.25. Example 61 A suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o 25 methoxyphenoxy)-2-(4-pyridyl)-4-pyrimid inyl]-2-pyridine sulfonamide (Example 3), 10 mg of DMAP and 25 pl 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 30 citric acid and 2x50 ml of water. The organic phase was dried over MgSO 4 and evaporated. The crude product was purified by column chromatography on silica gel eluting first with hexane:ethyl acetate 1:1, then with DCM WO 01/46156 PCT/EPOO/12743 - 62 containing 4% of methanol to give 47 mg of phenylcarbamic acid 4-[6-(5 methylpyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl pyrimidin-4-yloxy]-but-2-ynyl ester as a slightly yellow solid. LC-MS: tR = 4.80 min, [M+1]* = 653.37, [M-1]~ = 651.33. 5 Example 62 37 mg of (3-methylphenyl)-carbamic acid 4-[6-(5-methylpyridine-2 sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2 10 ynyl ester was obtained as a yellow solid starting from 50 mg of 5-methyl-N [6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4 pyrimidinyl]-2-pyridine sulfonamide (Example 3) and 25 pLl of 3 methylphenylisocyanate following the procedure given in Example 61. MS: tR = 4.95 min, [M+1]* = 667.42, [M-I]- = 665.30. 15 Example 63 38 mg of (2-fluorophenyl)-carbamic acid 4-[6-(5-methylpyridine-2 sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2 20 ynyl ester was obtained as an off-white foam starting from 50 mg of 5-methyl N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4 pyrimidinyl]-2-pyridine sulfonamide (Example 3) and 25 ltl of 2 fluorophenylisocyanate following the procedure given in Example 61. MS: tR 4.79 min, [M+1]* = 671.34, [M-1]~ = 669.28. 25 Example 64 42 mg of (4-fluorophenyl)-carbamic acid 4-[6-(5-methylpyridine-2 sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2 30 ynyl ester was obtained as an off-white foam starting from 50 mg of 5-methyl N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4 pyrimidinyl]-2-pyridine sulfonamide (Example 3) and 25 pl of 4- WO 01/46156 PCT/EPOO/12743 - 63 fluorophenylisocyanate following the procedure given in Example 61. MS: tR = 4.89 min, [M+1]* = 671.34, [M-1]~ = 669.28. Example 65 5 38 mg of 2-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5 (2-methoxy-phenoxy)-2-pyrid in-4-yl-pyrimid in-4-yloxy]-but-2-ynyl ester was obtained as a white powder starting from 50 mg of 5-methyl-N-[6-(4-hydroxy 2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine 10 sulfonamide (Example 3) and 50 mg of 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) according to the procedure given in Example 58. MS: tR = 4.32 min, [M+1]* = 654.39, [M-1]- = 652.33. 15 Example 66 18 mg of 2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2 sulfonylamino)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yloxy] 20 but-2-ynyl ester was obtained as a white solid starting from 50 mg of 5 isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2 pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 4) and 28 mg of 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) according to the procedure given in 25 Example 58. MS: tR = 4.84 min, [M+1]* = 683.41. Example 67 28 mg of 2-pyrazinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2 30 sulfonylamino)-5-(2-methoxy-phenoxy)-2-(2-pyrimid inyl)-pyrimid in-4-yloxy] but-2-ynyl ester was obtained as a slightly yellow solid starting from 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2- WO 01/46156 PCT/EPOO/12743 - 64 pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 4) and 50 mg of pyrazine-2-carbonyl azide (prepared from pyrazin-2-carboxylic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example 58. LC-MS: tR = 4.67 min, [M+1]* = 684.42, [M-1]- = 682.39. 5 Example 68 24 mg of 2-pyridinyl-carbamic acid 4-[6-(4-tert.butylbenzenesulfonylamino)-5 (2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was 10 obtained as a slightly yellow solid starting from 50 mg of 4-tert.-butyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimid inyl)-4 pyrimidinyl]benzene sulfonamide (Example 5) and 50 mg of 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example 58. LC-MS: tR 15 5.44 min, [M+1]* = 696.43, [M-1]- = 694.35. Example 69 39 mg of 2-pyrazinyl-carbamic acid 4-[6-(4-tert.butylbenzenesulfonylamino)-5 20 (2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as a slightly yellow solid starting from 50 mg of 4-tert.-butyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4 pyrimidinyl]benzene sulfonamide (Example 5) and 50 mg of pyrazine-2 carbonyl azide (prepared from pyrazin-2-carboxylic acid according to Chem. 25 Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example 58. LC-MS: tR = 5.25 min, [M+1]* = 697.44, [M-1]- = 695.35. Example 70 30 To a solution of 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide (Example 7d) in 5 ml of dry chloroform 25 l of phenyl isocyanate followed by 20 mg of WO 01/46156 PCT/EPOO/12743 -65 DMAP was added. The solution was stirred at 650C for 3 h. The solvent was removed partially under reduced pressure and the remaining solution was purified by column chromatography on 20 g of silica gel eluting with hexane : ethyl acetate 2:1. This gave 35 mg of phenyl-carbamic acid 4-[6-(5-isopropyl 5 pyridine-2-su lfonylamino)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yloxy] but-2-ynyl ester as a colourless foam. LC-MS: tR 5.62 min, [M+1]* = 618.33, [M-1]~ = 616.45. Example 71 10 43 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-su lfonylamino)-5 (2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as a white foam starting from 50 mg of 5-isopropyl-N-[6-(4-hydroxy 2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2 15 pyridine sulfonamide (Example 9) and 30 [l of phenylisocyanate following the procedure given in Example 53. LC-MS: tR = 5.57 min, [M+1]* = 689.38, [M-1]~ = 687.49. Example 72 20 142 mg of 2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2 sulfonylamino)-5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxyl but-2-ynyl ester was obtained as a colourless foam starting from 150 mg of 5 isopropyl-N-[6-(4-hyd roxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N 25 morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 9) and 100 mg of 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example 58. LC-MS: tR = 5.37 min, [M+1]+ = 690.53, [M-1]- = 688.38. 30 Example 73 WO 01/46156 PCT/EPOO/12743 - 66 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 pl of morpholine-4-carbonyl chloride. The mixture was stirred 5 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. The aqueous phase was extracted two more times with ethyl acetate, the combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The crude product was purified on prep. tIc-plates 10 with toluene:ethyl acetate 1:1 to give 152 mg of morpholine-4-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-(N morpholino)-pyrimidin-4-yloxy]-but-2-yny ester as a beige foam. LC-MS: tR = 5.26 min, [M+1]* = 683.43, [M-1]- = 681.57. 15 Example 74 170 mg of dimethyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino) 5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimid in-4-yloxy]-but-2-ynyl ester was obtained as white crystals (from 2-propanol/methanol) starting from 570 20 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 9) and 52 pl of diemthylcarbamic acid chloride following the procedure given in Example 72. LC-MS: tR = 5.29 min, [M+1]* = 641.41, [M-1]- = 639.56. 25 Example 75 39 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5 (2-methoxy-phenoxy)-pyrimidin-4-yloxy]-but-2-yny ester was obtained as a colourless foam starting from 40 mg of 5-isopropyl-N-[6-(4-hydroxy-2 30 butynyloxy)-5-(o-methoxyphenoxy)-4-pyrimid inyl]-2-pyrid ine sulfonamide (Example 13) and 50 pl of phenylisocyanate following the procedure given in Example 53. LC-MS: tR = 5.38 min, [M+1]* = 604.32, [M-1]~ = 602.25.
WO 01/46156 PCT/EPOO/12743 - 67 Example 76 50 mg of phenyl-carbamic acid 4-[6-(4-tert.-butyl-benzene-sulfonylamino)-5 5 (2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as a colourless foam starting from 50 mg of 4-tert.-butyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimid in-4 yl]-benzene sulfonamide (Example 14) and 50 pil of phenylisocyanate following the procedure given in Example 53. LC-MS: tR = 6.07 min, [M+1]= 10 702.50, [M-1]~ = 700.40. Example 77 39 mg of 2-pyridinyl-carbamic acid 4-[6-(4-tert.-butyl-benzene-sulfonylamino) 15 5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as a colourless foam starting from 50 mg of 4-tert.-butyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4 yl]-benzene sulfonamide (Example 14) and 50 mg of 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 20 1651-1657) according to the procedure given in Example 58. MS: tR = 5.63 min, [M+1]* = 703.46, [M-1]- = 701.38. Example 78 25 44 mg of n-butyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-(2 methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as a white solid starting from 50 mg of 5-methyl-N-[6-(4-hydroxy-2 butynyloxy)-5-(2-methoxyphenoxy)-2-(N-morphoino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 15) and 50 jLl of n-butylisocyanate according to the 30 procedure given in Example 53. MS: tR = 5.24 min, [M+1]* = 641.47, [M-1] = 639.39.
WO 01/46156 PCT/EPOO/12743 - 68 Example 79 53 mg of cyclohexyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino) 5-(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester 5 was obtained as a colourless foam starting from 50 mg of 5-methyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl] 2-pyridine sulfonamide (Example 15) and 100 tl of cyclohexylisocyanate according to the procedure given in Example 53. MS: tR = 5.32 min, [M+1]* = 667.48, [M-1]- = 665.41. 10 Example 80 54 mg of phenyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-(2 methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester was 15 obtained as a colourless foam starting from 50 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl] 2-pyridine sulfonamide (Example 15) and 50 pl of phenylisocyanate according to the procedure given in Example 53. MS: tR = 5.32 min, [M+1]* = 661.43, [M-11 = 659.38. 20 Example 81 36 mg of 2-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5 (2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester 25 was obtained as a white powder starting from 50 mg of 5-methyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl] 2-pyridine sulfonamide (Example 15) and 50 mg of 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) according to the procedure given in Example 58. MS: tR = 4.90 30 min, [M+1]* = 662.17, [M-1]- = 660.12.
WO 01/46156 PCT/EPOO/12743 - 69 Example 82 40 mg of 3-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5 (2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester 5 was obtained as a white powder starting from 50 mg of 5-methyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl] 2-pyridine sulfonamide (Example 15) and 50 mg of nicotinic acid azide (prepared from nicotinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) according to the procedure given in Example 58. MS: tR 4.19 10 min, [M+1]* = 662.39, [M-1]- = 660.59. Example 83 7 mg of 4-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5 15 (2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as a white solid starting from 50 mg of 5-methyl-N-[6-(4 hyd roxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morphol ino)-4-pyrimid inyl] 2-pyridine sulfonamide (Example 15) and 50 mg of isonicotinic acid azide (prepared from isonicotinic acid according to Chem. Pharm. Bull. 25 (1977) 20 1651-1657) according to the procedure given in Example 58. MS: tR = 3.89 min, [M+1]* = 662.39, [M-1]- = 660.33. Example 84 25 204 mg of 4-pyrazinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino) 5-(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-yny ester was obtained as a white solid starting from 50 mg of 5-methyl-N-[6-(4 hydroxy-2-butynyloxy)-5-(2-methoxyphenoxy)-2-(4-morpholino)-4-pyrimidinyl] 2-pyridine sulfonamide (Example 15) and 50 mg of pyrazine-2-carbonyl azide 30 (prepared from pyrazin-2-carboxylic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) following the procedure given in Example 58. MS: tR 4.80 min, [M+1]* = 663.43, [M-1]- = 661.36.
WO 01/46156 PCT/EPOO/12743 - 70 Example 85 36 mg of phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5 5 (p-tolyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as an off-white foam starting from 60 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4 pyrimidinyl]-2-pyridine sulfonamide (Example 16) and 50 pl of phenylisocyanate following the procedure given in Example 53. MS: tR = 5.50 min, [M+1]* = 572.36, [M-1]~ = 570.30. 10 Example 86 79 mg of N-methyl-N-phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2 sulfonylamino)-5-(p-tolyl)-pyrimidin-4-yloxy]-but-2-ynyl ester was obtained as 15 a beige foam starting from 230 mg of 5-isopropyl-N-[6-(4-hydroxy-2 butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 16) and 95 mg of N-methyl-N-phenyl-carbamic acid chloride following the procedure given in Example 72. LC-MS: tR = 5.44 min, [M+1I] = 586.33, [M-1]~ = 584.50. 20 Example 87 To a solution of 300 mg of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2 (4-pyridyl)-4-pyrimidinyll-2-pyridine sulfonamide (Example If) and 1.47 g of 4 methoxy-2-butynol (prepared starting from 2-butyn-1,4-diol and 25 dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28 (1955), 80-83) in 15 ml of DMF was carefully added 234 mg of 55% NaH in mineral oil. The brown solution stirred for 24 h at room temperature before further 120 mg of 55% NaH in mineral oil was added. Stirring was continued for 24 h. The mixture was diluted with 100 ml of 10% aqueous citric acid and 30 extracted four times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, dried over MgSO 4 and evaporated. The crude product was purified by column chromatography on WO 01/46156 PCT/EPOO/12743 - 71 silica gel eluting with ethyl acetate to give 154 mg of 5-isopropyl-N-[6-(4 methoxy-but-2-ynyloxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] 2-pyridine sulfonamide as a yellow solid. LC-MS: tR = 4.84 min, [M+1]* = 576.42, [M-1]- = 574.37. 5 Example 88 To a solution of 300 mg of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2 (4-pyridyl)-4-pyrimid inyl]-2-pyrid ine sulfonamide (Example 1f) and 502 mg of 10 4-phenoxy-2-butyn-1-ol (prepared starting from phenyl-propargylether and para-formaldehyde following the procedure given in J. Chem. Soc. Perkin Trans. 1, 1991, 1721-1727) in 15 ml of THF was added 228 mg of 55% NaH in mineral oil. The orange suspension was stirred at room temperature for I h before it was diluted with 100 ml of 10% aqueous citric acid. The mixture was 15 extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed with 50 ml of water, dried over MgSO 4 and evaporated. The crude product was purified by chromatography on prep. tic-plates with ethyl acetate:methanol:sat. aqueous ammonia 8:2:1 to give 241 mg of 5 isopropyl-N-[6-(4-phenoxy-but-2-ynyloxy)-5-(2-methoxy-phenoxy)-2-pyridin-4 20 yl-pyrimidin-4-yl]-2-pyridine sulfonamide as a slightly yellow foam. LC-MS: tR = 5.95 min, [M+1]* = 666.58, [M-I]~ = 664.62 Example 89 25 To a mixture of 250 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2 (2-pyrimidinyl)-4-pyrimi-dinyl]benzene sulfonamide (Example 5a) and 1.11 g of 4-methoxy-2-butynol (prepared starting from 2-butyn-1,4-diol and dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28 (1955), 80-83) in 15 ml THF was added 177 mg of 55% NaH in mineral oil. 30 The suspension was stirred for 16 h at reflux. The reaction mixture was cooled, diluted with 100 ml 10% aqueous citric acid and extracted 4 times with 50 ml of ethyl acetate. The combined organic phases were washed with WO 01/46156 PCT/EPOO/12743 - 72 water, dried over MgSO4 and evaporated. The crude product was purified by chromatography on prep. tic-plates with ethyl acetate: methanol:sat. aqueous ammonia 8:2:1 to give 116 mg of 4-tert.-butyl-N-[6-(4-methoxy-2-butynyloxy) 5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide 5 as a slightly yellow foam. LC-MS: tR = 5.19 min, [M+1]* = 590.40, [M-1]- = 588.39 Example 90 10 To a mixture of 260 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2 (2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (Example 5a) and 1.50 g of 4-phenoxy-2-butyn-1-ol (prepared starting from phenyl-propargylether and para-formaldehyde following the procedure given in J. Chem. Soc. Perkin Trans. 1, 1991, 1721-1727) in 15 ml THF was added 184 mg of 55% NaH in 15 mineral oil. The suspension was stirred for 1 h at reflux. The reaction mixture was cooled, diluted with 100 ml 10% aqueous citric acid and extracted 4 times with 50 ml of ethyl acetate. The combined organic phases were washed with water, dried over MgSO 4 and evaporated. The crude product was purified by chromatography on prep. tic-plates with ethyl acetate:methanol:sat. 20 aqueous ammonia 8:2:1 to give 82 mg of 4-tert.-butyl-N-[6-(4-phenoxy-2 butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimid inyl]benzene sulfonamide as a slightly yellow foam. LC-MS: tR = 5.60 min, [M+1]* = 652.63, [M-1]- = 650.58. 25 Example 91 To a solution of 390 mg of 4-benzyloxy-2-butyn-1-ol (prepared starting from 2 butyn-1,4-diol and benzylbromide in analogy to a procedure reported in Tetrahedron Lett. 38 (1997), 7887-7890) in 5 ml DMF:THF 1:1 was added 97 30 mg of 55% NaH in mineral oil. After the evolution of gas had ceased, 250 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4 pyrimidinyl]benzene sulfonamide (Example 5a) was added and the mixture WO 01/46156 PCT/EPOO/12743 - 73 was stirred at 50 0 C for 20 h before it was diluted with 75 ml of ethyl acetate. The mixture was washed with 75 ml of 10% aqueous citric acid and 75 ml of water, and evaporated. The crude product was purified by chromatography on prep. tic-plates with ethyl acetate:methanol:sat. aqueous ammonia 10:2:1 to 5 give 125 mg of 4-tert.-butyl-N-[6-(4-benzyloxy-2-butynyloxy)-5-(o-methoxy phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide as a yellow foam. LC-MS: tR = 5.93 min, [M+1]* = 666.47, [M-1]~ = 664.63. Example 92 10 184 mg of 4-tert.-butyl-N-[6-(4-(4-methylbenzyloxy)-2-butynyloxy)-5-(o methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was obtained as a yellow foam starting from 250 mg of 4-tert.-butyl-N-[6-chloro-5 (o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyllbenzene sulfonamide 15 (Example 5a) and 421 mg of 4-(4-methylbenzyloxy)-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and 4-methylbenzylbromide in analogy to a procedure reported in Tetrahedron Lett. 38 (1997), 7887-7890) following the procedure given in Example 91. LC-MS: tR = 6.11 min, [M+1]* = 680.51, [M-1] = 678.61. 20 Example 93 Crude 4-tert.-butyl-N-[6-(4-(3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxy phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was obtained 25 starting from 300 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2 pyrimidinyl)-4-pyrimidiny]benzene sulfonamide (Example 5a) and 1096 mg of 4-(3-methoxybenzyloxy)-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and 3-methoxybenzylbromide in analogy to a procedure reported in Tetrahedron Left. 38 (1997), 7887-7890) following the procedure given in 30 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 WO 01/46156 PCT/EPOO/12743 - 74 resulting oil was dissolved in 10 ml of diethyl ether and treated with pentane. The precipitate was collected and dried to give 102 mg of 4-tert.-butyl-N-[6-(4 (3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2 pyrimidinyl)-4-pyrimid inyl]benzene sulfonamide as an almost white powder. 5 LC-MS: tR = 5.74 min, [M+1]* = 696.40, [M-1]~ = 694.32. Example 94 To a mixture of 250 mg of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2 10 (N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 9c) and 1.2 g of 4-methoxy-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28 (1955), 80-83) was added 192 mg of 55% NaH in mineral oil. After evolution of gas had ceased, the brown suspension was refluxed for 16 h. Further 96 15 mg of 55% NaH in mineral oil was added and heating and stirring was continued for another 3 h. The mixture was cooled, diluted with 50 ml of 10% aqueous citric acid and extracted 4 times with 50 ml of ethyl acetate. The combined organic phases were washed with water, dried over MgSO 4 and evaporated. The crude product was purified by column chromatography on 20 silica gel eluting with hexane:ethyl acetate 1:3 and precipitated from diethyl ether to give 114 mg of 5-isopropyl-N-[6-(4-methoxy-2-butynyloxy)-5-(o methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide as a white powder. LC-MS: tR = 5.19 min, [M+1]* = 584.46, [M-1]- = 582.38. 25 Example 95 To a mixture of 300 mg of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl] benzene sulfonamide (Example 12c) and 1.8 g of 4-methoxy-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and dimethylsulfate following the 30 procedure given in Bull. Chem. Soc. Japan 28 (1955), 80-83) was added 288 mg of 55% NaH in mineral oil. After evolution of gas had ceased, the brown suspension was stirred at room temperature for 24 h. Another 288 mg of 55% WO 01/46156 PCT/EPOO/12743 - 75 NaH in mineral oil was added and the mixture was stirred at 600C for 18 h. The mixture was cooled, diluted with 50 ml of 10% aqueous citric acid and extracted 4 times with 50 ml of ethyl acetate. The combined organic phases were washed with water, dried over MgSO 4 and evaporated. The crude 5 product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 1:1 and precipitated from diethyl ether to give 213 mg of 4-tert.-butyl-N-[6-(4-methoxy-2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR = 5.61 min, [M+1]* = 480.30, [M-1] 478.39. 10 Example 96 To a mixture of 282 mg of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl] benzene sulfonamide (Example 12c) and 1.10 g of 4-phenoxy-2-butyn-1-ol 15 (prepared starting from phenyl-propargylether and para-formaldehyde following the procedure given in J. Chem. Soc. Perkin Trans. 1, 1991, 1721 1727) in 15 ml THF was added 271 mg of 55% NaH in mineral oil. The suspension was stirred for 4 h at reflux. The reaction mixture was cooled, diluted with 100 ml 10% aqueous citric acid and extracted 4 times with 50 ml 20 of ethyl acetate. The combined organic phases were washed with water, dried over MgSO 4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with heptane:ethyl acetatel:1 and precipitated from diethyl ether to give 151 mg of 4-tert.-butyl-N-[6-(4-phenoxy 2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white 25 powder. LC-MS: tR = 6.34 min, [M+1]* = 542.48, [M-1]~ = 540.15.

Claims (7)

1. Compounds of the formula I 0 0 R NH N R 3 general formula I R N 0 5 OR 2 wherein R' represents phenyl; mono-, di- or tri-substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower 10 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; 15 five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms which may be mono- or di-substituted with halogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl, halogen, trifluoromethyl; 2-pyridyl; 5 substituted 2-pyridyl substituted with lower alkyl, lower alkoxy; benzyl; mono-, di- or tri-substituted benzyl substituted with phenyl, halogen, hydroxy, lower 20 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, WO 01/46156 PCT/EPOO/12743 -77 trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms; aryl; heteroaryl; 5 R 2 represents hydrogen; lower alkyl; trifluoromethyl; phenyl; mono-, di- or tri substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, lower alkenyi, 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, 10 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 halogen, lower alkyl, lower alkoxy; benzyl; mono-, di- or tri-substituted benzyl 15 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, trifluoromethyl, trifluoromethoxy, cycloalkyl, 20 hydroxy-cycloalkyl; 2-pyrimidyl; mono- or di-substituted 2-pyrimidyl substituted with lower alkyl, lower alkoxy, hydroxy-lower alkyl, halogen, trifluoromethyl, five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms; aryl; heteroaryl; heterocyclyl; a group of the formula 25 -C(A)-B-Ra, wherein A represents 0 or S; B represents NH or a bond; and 30 Ra represents lower alkyl; cycloalkyl; trifluoromethyl; phenyl; mono-, di- or tri substituted phenyl substituted with phenyl, halogen, hydroxy, lower alkyl, WO 01/46156 PCT/EPOO/12743 - 78 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 5 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 halogen, lower alkyl, lower alkoxy, trifluoromehtyl, trifluoromethoxy; six membered heteroaryl rings containing one or two nitrogen atoms which may 10 be mono-, di- or tri-substituted with halogen, lower alkyl, lower akyloxy, trifluoromethyl; R 3 represents hydrogen, lower alkyl, phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkynyl, lower 15 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, 20 hydroxy, hydroxy-lower alkyl, cyano, carboxyl; R 4 represents hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lower alkylthio-lower alkyl, hydroxy-lower alkyl, lower alkyl oxy-lower alkyl, hydroxy-lower alkyl-oxy-lower alkyl, amino-lower alkyl, lower 25 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 alkenyloxy, trifluoromethyl, 30 trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl; aryl; aryl-amino; arylthio; aryloxy; aryl-lower alkyl; heteroaryl; heterocyclyl; WO 01/46156 PCT/EPOO/12743 - 79 X represents oxygen; sulfur; NH or a bond; and pure enantiomers, enantiamerically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric 5 racemates and pharmaceutically acceptable salts thereof.
2. Compounds of formula I wherein R', R 2 , and R 4 are as defined in claim 1, and wherein 10 R 3 represents phenyl; mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, trifluoromethoxy, halogen; X represents oxygen or a single bond, 15 and pharmaceutically acceptable salts thereof.
3. Compounds of formula 11 NH R5 N R3 formulaII R4 N 0 0R 2 20 wherein R 2 , Ra, R 4 , and X are as defined in formula I in claim 1, and R 5 represents lower alkyl, and pharmaceutically acceptable salts of compounds of formula 11. WO 01/46156 PCT/EPOO/12743 - 80 4. Compounds of formula IlIl R 1 NH N R3 formula III R4 N 0 O N R 6 N 5 R 8 wherein R 1 , Ra, R 4 , and X are as defined in formula I in claim 1, and R 6 , R 7 , and R 8 , each and independently represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower 10 alkynyloxy, halogen, trifluoromethyl, trifluoromethoxy, lower alkylthio; and pharmaceutically acceptable salts thereof.
5. Compounds of formula IV 15 WO 01/46156 PCT/EPOO/12743 - 81 00 R NH N R formula IV 4) R N 0 H O N 1-Ra 0 wherein R 1 , R 3 , R 4 , R' and X are as defined in formula I above, 5 and pharmaceutically acceptable salts thereof.
6. Compounds of formula I wherein R 1 , R 3 , R 4 , and X are as defined in claim 1, and wherein R 2 represents lower alkyl, 10 and pharmaceutically acceptable salts thereof.
7. The compounds as described as final products in any of the Examples 1 to
96. 15 8. Pharmaceutical compositions for the treatment of disorders which are associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris and proliferative disorders such as cancer, containing a compound of any one of claims 1 to 7 20 and usual carrier materials and adjuvants. WO 01/46156 PCT/EPOO/12743 - 82 9. Pharmaceutical compositions for the treatment of disorders which are associated with a role of endothelin, such as migraine, asthma or inflammatory disorders, containing a compound of any one of claims 1 to 7 and usual carrier materials and adjuvants. 5 10. The compounds of any one of the claims I to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris, proliferative disorders such as cancer, migraine and 10 inflammatory disorders. 11. The compounds of any one of the claims 1 to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require mixed ETA and ETB blocking for treatment. 15 12. The compounds of any one of the claims 1 to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require selective ETA blocking for treatment. 20 13. The compounds of any one of the claims I to 7 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require selective ETB blocking for treatment. 14. The use of one or more compounds of any one of claims 1 to 7 as active 25 ingredients for the production of pharmaceutical compositions for the treatment of disorders associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris and proliferative disorders such as cancer. 30 15. The use of one or more compounds of any one of claims 1 to 7 as active ingredients for the production of pharmaceutical compositions for the WO 01/46156 PCT/EPOO/12743 - 83 treatment of disorders associated with endothelin activities, such as migraine, asthma or inflammatory disorders. 16. A process for the manufacture of pharmaceutical compositions for the 5 treatment of disorders associated with a role of endothelin containing one or more compounds as claimed in any one of claims 1 to 7 as active ingredients which process comprises mixing one or more active ingredient with pharmaceutically acceptable excipients in a manner known per se. 10 17. The invention as hereinbefore described.
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