The preisent invention relates to novel pyrimidine-sulfamides of the genera) formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I, and especially their use as endothelin receptor antagonists.
Endothetins (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). Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions {McMJIIen MA et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory celts, fibrosis, cad proliferation and ced differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46:328).
Two endothelin receptors have been cloned and characterized in mamnrials (ETA. ETB) (Aral 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 and ET-2 Uian for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohistein EIH et al.: Drug Dev Res (1993) 29:108). In contrast, the ETB receptor has equivalent affinity for the three endothelin isopeptides and binds the linear fomi of endothelin, tetra-ala-endothem, and sarafotoxin S6C (Ogawa Y et ai: BSRC (1991) 178:248). This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain. The ETB receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ETB receptor from smootfi muscle ceils exerts vasoconstricting actions (Sumner MJ el al.; Bril J PharmacD) (1992)

107:858). ETA and ETB receptors are highly similar in structure and belong to the superfamilycf G-proteIn coupted 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, pulmonary hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart faiJure, 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 systemic hypertension, rteurogenic inflammation, renal failure and myocardial infarction.
Today, only one endothelin receptor antagonist (Tracleer''*') is marketed and several are in dinical trials. However, some of these molecules possess a number of weaknesses such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics, or safety problems (e.g. liver enzyme increases). Furthermore, the contribution of differing ETA / ETB receptor blockade to the clinical outcome is not known. Thus, tailoring of the physicochemical and pharmacokinetic properties and the selectivity profile of each antagonist for a given clink:al indication is mandatory. So far, no endothelin receptor antagonists with a pyrimidine core stnicture containing a sulfamide unit, have been reported [2, 3, 5, 6. 8]. Surprisingly, we have discovered a new class of substituted pyrimidines of the structure below and found that they allow the specific tailoring described above and, in addition, compounds exhibiting mixed as well as ETA-selective binding profiles have been identified.
The inhibitory activity of the compounds of general formula I on endothelin receptors can be demonstrated using the test procedures described hereinafter:

For the > valuation of the potency and efficacy of the compounds of the general formula I the following tests were used:
1) InhibiJon of endothelin binding to membranes from CHO cells carrying human E T receptors:
For com letition binding studies, membranes of CHO cells expFessing human recombir ant ETA or ETB receptors were used. Microsomal membranes from recombir ant CHO cells were prepared and the binding assay made as previously describet (Breu V., et al, FEBS Lett 1993; 334:210).
The assc y was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, inc uding 25 mM MnC 2, 1 mM EDTA and 0.5% (wA/) BSA in polypropylene microtiter plates. Membrar es containing 0.5 ug protein were incubated for 2 h at 20''C with 8 pM [^^*I]ET-1 (4000 cpm) and increasirig concentrations of unlabelled antagonists. Maximun and minimum binding were estimated in samples without and with 100 nM ET-1 respectively. After 2 h, the membranes were filtered on fiiiterplates containin | GF/C filters (Unifilterplates from Canben'a Packard S.A Zurich, Switzeria id). To each well, 50 uL of scintillation cocktail was added (MicroScint 20, Canb ;rra Packard S.A. ZQrich, Switzerland) and the filter plates counted in a microplat! counter (TopCount, Canberra Packard S.A. ZCirk:h, Switzerland).
All the te X compounds were dissolved, diluted and added in DMSO. The assay was run in the presence of 2.5% DMSO which was found not to interfere signifrcan ly with the binding. tCso was calculated as the concentration of antagonis: inhibiting 50 % of the specific binding of ET-1. For reference compoum is, the following IC50 values were found; ETA cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3: ETB celts: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) or ET-3.

The IC50 values obtained with compounds of general formula t are given in Table 1.

The functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ETA receptors] and of the contraction induced by sarafotoxin S6c on rat tracheal rings (ETB receptors). Adult Wistar rats were anesthetized and exsanguinated. The thoracic aorta or trachea were excised, dissected and cut in 3-5 mm rings. The endotheliunrt/eptthelium was removed by gentle rubbing of the intimal surface. Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCI 115. KCI 4.7, MgSO« 1.2. KH2PO4 1.5. NaHCOa 25, CaClz 2.5, glucose 10} kept at 37°C and gassed with 95% O2 and 5% CO2. The rings were connected to force transducers and isometric tension was recorded {EMKA Technologies SA, Paris, France). The rir>gs were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (iaorta) or sarafotoxin S6c (trachea) were added after a 10 min Incubation with the test compound or Its vehicle. The functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC50 induced by different concentrations of test compound. ECso is the concentraton of endothelin needed to get a half-maximal contraction. pA2 is the

negative logarithm of the antagonist concentration which induces a two-fold shift in the ECso value.
The pA2 values obtained with connpounds of formula I are given in Table t'..

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 endothelin. Exa-nples of such diseases are hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers and portal hypertension. They can also be used in the treatment or prevention of atherosclerosis, restenosis after balloon or stent anfjioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, therapy and prophylaxis of diabetic complications, complicjitions of vascular or cardiac surgery or after organ transplantation, compli«itions of cyclosporin treatment, pain, hyperiipidemta as well as other diseases, presently known to be related to endothelin.

The compounds can be administered orally, rectally, parenterally. e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol. Examples of applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
Preferred applications are intravenous, intra-muscular. or oral administrations as well as eye drops. The dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1 - 50 mg / kg body weight per day are considered. The preparations with compounds can contain inert or as well pharmacodyiamically active excipients. Tablets or granules, for example, could contain a njmtier of binding agents, filling excipients, carrier substances or diluents.


R^ represents hydrogen: trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; lower alkyk}xy-tower alkyloxy; hydroxy-lower alkyloxy; lower alkyl-sjlfinyt; lower alkylthio; lower alkytthio-lower alkyl; hydroxy-lower alkyl; lower alkyloxy-lower alkyl; hydroxy-lower alkyloxy-lower alkyl; hydroxy-lower alkylamino; lower alkylamino-lower alkyl; amino; di-lower alkylamino; [N-(hydroxy-tower alkyl)-N-(lower alkyl)]-amino; aryt; arylamino; aryl-lower alkylamino; arylthio; aryHower alkylthio; aryloxy; aryl-lower alkyloxy; aryl-lower alkyl; arylsulfinyl; heteroaryl; heteroaryloxy; heteroarylamino; heteroarylthio; heteroaryl-lower alkyl; heteroar>^-sulfinyl; heterocyclyl; heterocyclyl-lower alkyloxy; beterocyclyloxy; heterocydyl-amino; heterocyclyl-lower alkylamino; heterocyclylthio; heterocyclyl-lower alkyl¬thio; heterocyclyl-lower alkyl; heterocydylsuinnyl; cycloalkyi; cy do alkyloxy; cycloalkyl-lower alkyloxy: cycloalkylamino; cycloalkyl-lower alkylamino; cycloalkyl-thio; cycloalkyl-lower alkylthio; cyctoalkyl-lower alkyl; cycloalkylsulfinyl;
8

R* represents hydrogen or methyl;
X represents oxygen; sulfur -CHz- or a bond;
Y represents a bond, -0-; -NH-; -SO2-NH-; -NH-SO2-NH-; -0-CO-; -CO-0-; -O-CO-NH-; -NH-CO-0-: -NH-CO-NH-;
n represents the integers 2, 3, or 4;
m represents the integers 2, 3, or 4;
R* represents aryl, heteroaryl, lower alkyl, cycloalkyi, hydrogen;
and optically pure enantiomers. mixtures of enantiomers such as for example racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-forms and pharmaceutically acceptable salts thereof.
In the definitions of the general formula I - if not otherwise stated - the expression lower means straight and branched chain groups with one to seven cartxim atoms, preferably 1 to 4 cart>on atoms. Examples of lower atkyi and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tiirt.-butyl, pentyl, hexyl, heptyl, mettioxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy, Lower alkylendioxy-groups are preferably methylen-dioxy and ethylen-dioxy groups. Examples of lower alkanoyl-groups are acetyl, propanoyl artd butanoy^. Lower alkenyien means e.g.vinyien, propenylen and butenylen. Lower alken^ and lower alkynyl means groups like ethenyl. propenyl, butenyl, 2-methyl-propenyl, and ethirtyl, propinyl, butJnyl, pentinyi, 2-methyl-pentinyl. Lower alkenyloxy means allyioxy. vinyloxy and propenyloxy. The expression cycloalkyi means a saturated cyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycioheptyl, which may be substituted with lower alkyl. hydroxy-lower alkyl, amino-lower alkyl, and lower
9

atkoxy-lower alkyl groups. The expression heterocyclyl means saturated or unsaturated (but not aromatic), four, five-, six- or seven-membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be adequatly substituted with tower aikyl. lower alkoxy, e.g. piperidinyl, morphoNnyl, thiomorpholinyl, pir>eraziny1. tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyt, pyrrolidinyl, tetrahydrofuranyt. dfhydropyrrolyl, dihydroimidazolyf. dihydropyrazoiyl. pyrazolidinyl 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, benzo-fused six-membered aromatic rings containing one to three nitrogen atoms, five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, benzo-ftjsed five-membefed aromatic rings containing one oxygen or one niUogen or one sulfur atom, five membered aromatic- rings containlg an oxygen and nitrogen atom and benzo-fused derivatives thereof, five membered aromatic rings containing a sulfur and a nitrogen atom and benzo fused derivatives thereof, five- membered aromatic rings containing two nitrogen atoms and tsenzo fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring; e.g. furanyl, thienv4, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl. Imidazolyl, triazinyl, thiazinyl, thiazolyt. iso::hiazolyl, pyridazinyl, oxazolyl, isoxazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1.2,4-thiaidiazolyl, 5-thioxo-1,2,4-oxadia2olyl, 2-oxo-1,2,3,5-oxathiadiazD!yl, whereby such rings may be substituted with lower alkyl, lower alkenyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy, trifluoromethoxy, trifluoromethyl, carboxyl. carboxamidyl, thioamidyl, amidinyl, lower alkoxy-carbonyl, cyano. hydroxy-lower alkyl, lower alkyl-oxy-lower alkyl or another heteroaryl- or heterocydyl-ring (e.g.fH)- The expression aryl represents unsubstituted as well as mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphthyl rings whicti may be substituted with aryl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl. lower alkoxy, lower alkenyioxy, lower alkynyl-lower alkyl-oxy, lower alkenylen, lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl. hydroxy-lower alkyl-lower alkynyl. lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy,
10

trifluoromethyl, trifluoramethoxy, cycloalkyi, hydroxy-cycloalkyl, heteriDcyclyl. heteroaryl.
The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sutfuhc acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, rnethylsulfonic acid, p- toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
The compounds of the general formula I might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantixide, or ftosequinan; calcium-antagonists like diltiazem. nicardipine, nimodipine, verapamil or nifedipine; ACE-inhibitors like cllazapril, captopril, enalapril, lisinopril and the like; potassium channel activators like pinacidil; angiotensin II receptor antagonists like losartan, valsartan, irbesartan and the like; diuretics like
12

Preferred compounds are compounds of general formula I wherein R^ represents phenyl, mono- or di-substituted phenyl substituted with ethoxy, miethoxy or chlorine and X represents oxygen, and pharmaceutically acceptable sails thereof.
A second group of preferred compounds of general formula I are those wherein R^ represents phenyl, mono- or di-substituted phenyl substituted wilh ethoxy, methoxy or chlorine, X represents oxygen and R* represents ~(CH2)m-Y-R', and phamiaceuticaliy acceptable salts thereof.
A third group of preferred compounds of general formula I are those wherein R^ represents phenyl, mono- or di-subslituted phenyl substituted witn ethoxy, methoxy or chlorine, X represents oxygen and R' represents -ove.

Possibility C:
The compounds of general formula I may also be prepared by reacting a compound of Uie formula 5:


In Scheme 1 the synthetic procedure to prepare compounds of tlie general formula I is depicted by the description of the synthesis of Example 1. The other examples given in this document can be prepared via the same synthetic pathway, adapting the substituents and reaction conditions. The literature references given in [ ] are set forth at the end of this paragraph. The jamidines 1 were either commercial or were synthesized applying standard methodology [1] by reaction of the appropriate nitrile with sodium methylate in methanol followed by addition of ammonium chloride. The 2-substituted malonic estets 2 were prepared according to published procedures [2] by reacting dimethylchloromalonate 4 with the appropriate alcohol 3 [9] in acetone and potassium carbonate as base. The compounds 2 were dissolved In methanol, sodium methylate was added, and stirring was continued for aboL* 30 min followed by the addition of an amidine derivative 1. Stirring at ambient temperature was continued for another 8 h. After acidic work up the 4,6-dihydroxypyrimidines 5 could be isolated in yields of 70 to 90% [2]. Compounds 5 or the tautomeric form thereof were transformed into the dichloro derivatives 6 with phosphorus oxychloride in the presence of N.N-dimethylaniline at elevated temperatures {60-120'C) in yields of 40 to 75% [31- The dichlorides 6 were reacted with an excess of the appropriate sulfamide potassium salt 7 (prepared as outlined in Scheme 2) in DMSO at r.t. or 40 to 60*C to give the monochloro-pyrimidines 8 in yields of 70 to 90% either after recrystallization or chromatography. The pyrimidine derivatives 8 are then reacted with ethylene glycol (or another 1-fo-diol, or a mono alcohol) in the presence of a base like potassium tert.-butylate, sodium hydride or sodium at 80 - 110°C for 4 to 16 h to give compounds 9 as the first claimed compounds in yields of 50 to 70%. Compound 9 can be further transformed to compounds 11 by reaction with 2-chloro-5-bronTOpyrimidine 10 (or another suitable pyrimidine or pyridine derivative [16], [17]) in THF / DMF -5 / 1 at either r.t. or at 50 - 70'C in yields of 50 - 60%.


a) K2C03, acetone, reflux; b) NaOMe. MeOH, rt; c) POCb, N, N-dimethylaniline, 70-130X: d) 7. DMSO. rt; e) K-tert.-butylate, ethylene glycol. 75-100°C; 1) NaH. DMF and/or THF, 10, rt to fiO'C.

[1] W. GGhring, J. Schildknecht. M. Federspiel; Chimia. 1996, 50. 538 - 543.
[2] W. Neidhart, V. Breu, D. Bur, K. Burn, M. Clozel. G. Hirth. M. Mulktr, H. P. Wessel, H. Ramuz; Chimia, 1996. 50, 519 - 524 and references cited there.
[3] W. Neidhart. V. Breu. K. Burri, M. Clozel, G. Hirth. U. Klinkhammer. T. Giller. H. Ramuz; Bioorg. Med. Chem. Lett.. 1997, 7, 2223 - 2228. R. A. Nugent. S. T. Schlachter, M. J. Murphy, G. J. Cleek, T. J. Poel. D. G. Whishka, D. R. Graber, Y. Yagi, B. J. Keiser, R. A. Olmsted. L. A. Kopla, S. M. Swaney, S. M. Poppe, J. Mon-is. W. G. Tarpley, R. 0. Thomas; J. Med. Chem.. 1998, 41. 3793 - 3803.
[4] J. March; Advanced Organic Chemistry. 4* Ed., 1994, p. 499 and references cited there.
[5] EP 0 743 307 A1; EP 0 658 548 B1; EP 0 959 072 Al {Tanabe Seiyaku)
[6] EP 0 633 259 B1; EP 0 526 708 Al; WO 96/19459 (F. Hoffmann-LaRoche)
[7] for the Synthesis of 5-membered heterocycles see: Y. Kohara et al; J. Med. Chem.. 1996. 39.5228 - 5235 and references cited there.
[8] EP 0 882 719 Al (Yamanouchi Pharmaceutical Co., Ltd)
[91M. Julia. J. de Rosnay, Chim. Ther. 1965,4, 334-343.
[10] E. Cohen, B. Klartierg; J. Am. Chem. Soc, 1962, 84, 1994.
[Ill G. Weiss, G. Schulze. UebigsAnn. Chem.. 1969. 729, 40.
[121 R- Graf, Chem. Ber. 1959, 92. 509.
[13] J. A. Kloek. K. L. Leschinsky, J. Org. Chem.. 1976. 41, 4028.
24

(U]R. E. Olson.T. M. Sielecki, etal; J. Med. Chem.. 1999; 42,1178.
115] R. P. Dickinson, K. N. Dack. et al; J. Med. Chem., 1997; 40, 3442.
[16] D. G. Crosby. R. V. Berthold; J. Org. Chem., 1960; 25; 1916; D. J. EJrown, J. M. Lyall. Aust. J. Chem. 1964. 17. 794-802; H. C. Koppel. R. H. Springer. R. K. Robins, C. C. Cheng, J. Org. Chem. 1962. 27, 3614-3617; S. A. Jacobsen. S. Rodbotten, T. Benneche, J. Chem. Soc. Perkin Trans 1. 1999, 3265-3268; C. Maggjalj, G. Morini. F. Mossini. Farmaco. Ed.Sci. 1988. 43, 277-292; Patent France 1 549 494 (1968) (D. Razavi).
[17] US-4.233,294 1980.( Bayer AG)
[18] E. D. Morgan; Tetrahedron. 1967. 23.1735.
[19] M.J. Tozer, I. M. Buck et al.; Bioorg. Med. Chem. Lett., 1999, 9. 3103. G. Dewynter et al.; Tetrahedron. 1993. 49. 65.
[20] WO 02 53557 (Actelion Pharmaceuticals Ltd.)

Examples
The following examples Illustrate the invention. All temperatures are stated in "C.
List of Abbreviations;
AcjO actetic anhydride
aq. aqueous
CyHex cyclohexane
DBU 1.8-diazabicycloI5.4.01undec-7-en(1.5-5)
DCM dichloromethane
DMAP 4-dimetiiylaminopyndine
DMF dimathyifonnamide
DMSO dimethy^sulfoxide
EA ethyl acetate
EtsN triethylamine
Hex hexane
HV high vacuum conditions
KOtSu potassium tert. butylate
MCPBA m-chloroperbenzoic acid
min minutes
rflx reflux
rl room temperature
THF tetrahydrofuran
tf) retention time
The following compounds were prepared according to the pracedure described above and shown in Schemes 1 to 3. All compounds were characterized by 1H-NMR (300MH2) and occasionally by 13C-NMR (75MH2) (Varian Oxford. 300MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d - doublet, t = triplet; m = multiplet), by LC-MS' (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6x50 mm, Oevelosil RP Aqueous, 5 Jim, 120A. gradient: 5-95% acetonitrile in water, 1 min, with 0.04% trifluoroacettc

acid, flow: 4.5 m(/min) or LC-MS^ (Waters Micromass; ZMD-platform with ESi-probe with Alliance 2790 HT and DAD 996, column: 2x30 mm, Gromsil ODS4, 3 fim, 120A; gradient: C - 100% acetonitrile in water, 6 min. with 0.05% formic acid, flow: 0.45ml/min). tR is given in min; by TLC (TLC-plates from Merck. Silica get 60 F254) and occasionally by melting point.
Example 1
a) To a suspension of K2C03 (49.3 g) in acetone (100 ml) a solution of 2-chIoro-5-methoxy-phenoJ (37.7 g. boiling point 83-86''C. 13 mbar, [9]) was added dropwise at 40''C. The dropwise addition of dimethyl chioromalonate (43.6 g ) in acetone (100 ml) followed. The mixture was refluxed for 16 h before the solvent was removed under reduced pressure. The residue was taicen up fn water (400 mf) and extracted twice with DCM (400 ml). The organic extracts were dned over MgS04 and evaporated. Upon treatment of the oily residue with diethyl ether, the product crystallised. The crystals were collected, washed with a mixture of diethyl ether and hexane and dried to give 2-(2-chloro-5-methoxy-phenoxy)-malcnic acid dimethyl ester {53,73 g) as white crystals, 'H-NMR(CDCl3); 3,76(s, 3H), 3,86{s, 6H). 5.20(S, 1H). 6.53-6.58(m, 2H), 7.24-7.29(m. 1H).
b) A solution of 2-(2-ch(oro-5-methoxy-phenoxy)-ma(onic acid dimethyl ester (10 g) in methanol (100 ml) was added dropwise at O'C to a solution of NaOMe (5.6 g) in methanol (250 ml). The solution was stirred at rt for 2 h before fonriamidine hydrochloride (3.347 g) was added. The mixture was stirred at rt for 72 h. The solvent was removed under reduced pressure and the remaining residue was treated vflth 2N aq. HCl (150 ml). After stirring for 1h the solid material was

collected, washed with water and dried to give 5-(2-chloro-5-methoxy-phenoxy}-pyrimidine-4.6-drol (8.65 g) as a white powder. 'H-NMR(D6-DMSO): 3.6£i{s. 3H), 6.23, d, J=2.7, 1H). 6.58{dd, J=2.7. 8.8. 1H), 7.33(d, J=8.8. 1H). 8.07(s. 1H). 12,3(sbr, 2H).
c) To a solution of N, N-dimethylanillne (7.5 ml) in POCb (75 ml) 5-(2-chloro-5-methoxy-phenoxy)-pyrimkline-4,6-diol (8.65 g) was added in portions. The dark red to brown solution was heated to 120°C and stirred for 3h. The mixture was cooled and the excess of POCI3 was evaporated. The residue was treeited with ice-water (400 ml) and then extracted twice with EA (200 ml). The organic phase was washed with water and evaporated. The crude product was purified by column chromatography on silica gel eluting with heptaneiEA 7:3. The isolated product was suspended in methanol, filtered, washed with methanol, diethyl ether/hexane and dried to give 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine (8.23 g) as a pale yellow powder. V-NMR(CDCl3): 3.72(s, 3H), 6.05(d, J=2.7. 1H). 6.62(dd. J=2.7.8.8, 1H), 7.38(d, J=8,8. 1H). 8.69(s. 1H).
d) Tert.-butanol (5.56 g) is added dropwise to a solution of chlorosulfonyl isocyanate (10.61 g) in DCM (40 ml) while the temperature is maintained at 0-4'C. Stirring is continued for 30 min at 0°C before an ice-cold solution of 2-methoxy-ethylamine (5.63 g) and triethylamine (8.35 g) in DCM (80 ml) is added dropwise while the temperature of the mixture is itept at 0-2'C. Then the mixture is wamried to rt and stining is continued for 72 h. The mixture is washed ttvice with water (15 ml) and the aqueous phase was back extracted with DCM (50 ml). The organic phase was dried over MgSO* and evaporated. The remaining oil was dried under high vacuum before it was dissolved in 2-propanol (200 ml). The solution was cooled to -70'C and then treated with 5-6 N HCI in 2-prapano! (80 ml). The mixture was warmed to rt and stirring is continued for 18 h b(jfore the solvent was evaporated. The residue was dissolved in methanol (150 ml) and potassium tert.-butylate (8.42 g) was added in portions. The solution was stin-ed for 10 min and the solvent was evaporated. The remaining residue was dried under high vacuum to give 2-methoxyetharwsulfamic acid amide potassium salt

(15.51 g). ^H-NMR(D6-DMSO): 2.88-2.96 (m, 2H), 3.15 (s. 3H). 3.32-3.40Cm. 2H); '^C-NMR{D6-DMS0): 43.7, 58.6, 72.3.
e) A solution of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine {1.00 g)
and 2-methoxyethylsulfamic acid amide potassium salt (1.38 g) in DMSO (15 ml)
was stirred at rt for 18 h before it was diluted with a 10% aq. citric acid solution
(100 ml) and extracted twice with EA (100 ml). The organic phase was washed
twice with water (100 ml), dried over MgSO^ and evaporated. The product
crystallised from diethyl ether/hexane. The crystals were collected, washed with
additional diethyl ether and dried under high vacuum to give 2-riethoxy-
ethanesulfamic acid [6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yll-
amide (1.19 g) as a beige powder. LC-MS^ tR = 1.02 min. [M+1]* = 42;!.92. M-
NMR(CDCh): 3.20-3.28(m, 2H). 3.27(S, 3H). 3.44-3.50(m. 2H), 3.72(s. 3H), 5.90-
5.96(m br, 1H). 6.18(d, 2.9, 1H). 6.65(dd, 2.9. 8.8,1H), 7.37(d, 8.8,1H). 7.91(s br.
IH). 8.54(s, IH); ^^C-NMR(CDCb): 44.1. 56.1. 59.1. 70.2. 102.9, 110,0. 114.7.
131.5. 132.2. 151.3. 152.4. 152.8,153.9. 159.6.
f) To a suspension of 2-methoxy-ethanesulfamic acid [6-chloro-5-(2-(;hloro-5-methoxy-phenoxy>-pyrimidin-4-yl]-amide (1.17 g) in ethylene glycol (15 ml) was added potassium tert.-butlylate (3.10 g). The resulting clear solution was stirred at gO'C for 24 h. cooled to rt. diluted with EA (200 ml) and washed with 10% aq. citric acid (150 ml) and water (2x100 ml). The aqueous phase was extradsd once more with EA (100 ml). The combined organic phase was dried over MgS04 and evaporated. The residue was purified by column chromatography on silica gel eluting with hexaneiEA 1:3 to give 2-methoxy-ethanesulfamic acid [5-(2-i:hloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide (1.03 g) as a colourless glass. LC-MS': tR = 0.89 min. IM+ir= 448.92.
g) NaH (78 mg of a 55% dispersion in mineral oil) was added to a soluton of 2-methoxy-ethanesutfamic acid (5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide (200 mg) in DMF (6 ml). The mixture was stirred for 5 min before 5-bromo-2-chlore)-pyrimidine (172 mg) was added. The mixture was heated to SS'C and stirred for 3 h. diluted with EA (75 ml) and washed v/ith 10%

aq. citric acid solution (50 ml) and water (2x50 ml). The organic phase was evaporated and the residue was puriried by chromatography on prep, tic plates with heptane:EA 1:2 to give 2-methoxy-ethanesulfamic acid [6-I2-(5-bromo-pyrim id in-2-yloxy>-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a colourless foam. LC-MS^: IR = 1.07 min, [M+1]* = 604.95. ^H-NMR[CDCl3): 3.23(d, 5.3. 2H). 3.29(s. 3H). 3.50(t, 4.7. 2H), 3.67(S, 3H). 4.52-4.54{m, 2H}, 4.68-4.74(m, 2H). 5.93(t. 5.9. 1H), 6.24(d, 2.3. 1H). 6.52(dd. 2.9, 8.8. 1H), 7.23(d. 8.8, 1H), 7.58(s. 1H). 8.32(s. 1H), 8.45(s, 2H).
Example 2
a) To a solution of 4-bromophenylacetJc acid (50 g) in methanol (250 ml) thionyl chloride (34.2 ml) was added dropwise while the temperature of the reaction mixture was kept at O-S'C. Upon complete addition the cooling is remoi/ed and the mixture is allowed to warm to rt. Stirrrng was continued for 75 min before the solvent was removed in vacuo. The yellow oil was dissolved in benzene and evaporated. The residue was dissolved In EA, washed with water, brine, 2 N aq. NazCOa. and brine. The organic phase was dried over MgSO^ and evaporated and dried under high vacuum at 85''C for 30 min to give 4-bromophenylacetic acid methyl ester (52.4 g) as a yellow oil. 'H-NMR(D6-0MS0): 3.60(s, 3H), 3.67(s. 2H). 7.22{d. 8.5. 2H). 7.50(d, 8.5. 2H).
b) At 40*'C a solution of 4-bromophenylacetic acid methyl ester (52 g) in THF (100 ml) was carefully added over a period of 40 min to a suspension of NaH (15,6 g) in dry THF (450 ml). Stirring was continued for 70 min without heating and the temperature dropped to 27*C. The evolution of gas had stopped before dimethylcarbonate (76.42 ml) was added dropwise while the temperature of the

mixture was maintained at 29-31''C. Stirring was continued for 22 h at rt. The mixture was cooled to -10'C and then carefully neutralized to pH 6-7 with aq. HCI before bulk of the THF was removed in vacuo. The residue was dissolv&d in EA (700 ml), washed three times with 1 N aq. HCI and once with brine, dried over MgS04. Most of the EA was evaporated before hexane was added. The product crystallised over night at A'C. The crystals were collected, washed with hexane and dried to give 2-(4-bromophenyl>-malonic acid dimethyl ester (45.9 g) as pale yellow crystals. 'H-NMR(Ds-DMSO): 3.66(s, 6H), 5.07(s. IN), 7.30-7.34{m. 2H), 7.55-7.59(m.2H).
c) A solution of 2-(4-bromophenyl)-malonic acid dimethyl ester (11.73 g) in methanol (100 ml) was added at CC to a solution of sodium (2.83 g) in methanol (100 ml). The mixture was stirred for 18 h at rt before formamldine hydrochloride (4.10 g) was added. The suspension was stirred at rt for 4 h. The solvent was removed and the residue was suspended in 10% aq. citric acid (100 ml) and stirred for 10 min. The white precipitate was collected, washed with 10% aq- citric acid, water, evaporated three times from CyHex and dried under high vsicuum at 40''C to give 5-(4-bromophenyl)-pyrimidine-4,6-diol (9.90 g) as a pale beige powder. LC-MS: tR = 2.75 min. [M+H]* = 222.96, [M-H]- = 220.92. 'H-NMR(Dr DMSO): 7.43-7.48(m, 2H). 7.50-7.55(m, 2H), 8.13(s, IH), 12.1(s br. 2H).
d) To a suspension of 5-(4-bromophenyl)-pyrimidtne-4,6-dic^ (9.90 g) in POCI3 (130 ml) was carefully added N, N-dimethylaniline (13.5 ml). The mixiiure was heated to ISCC for 2 h. The dark brown solution was evaporated and the residue was poured into ice/water. The suspension was diluted with 2 N HCI and water and stirred for 20 min. The precipitate was collected and washed with water. The solid material was dissolved in EA. washed vinth 1 N aq. HCI and brine. The organic phase was dried over MgS04 and evaporated. The material was further purified by column chromatography on silica gel eluting with hexane:E^>i 95:5 to 1:1 followed by crystallisation from hexane/EA at-20°C to give 4,6-dichlore)-5-(4-bromophenyl>-pyrimidine (8.3 g) as paie yellow crystals. ^H-NMR(D6-DMS0): 7.39-7.44(m, 2H). 7.72-7.76(m, 2H). 8.94(s. IH).
31

e) A solution of 4,6-dichloro-5-(4-bromophenyl)-pyrimidine 1.79 mg) and 2-
methoxyethanesulfamic acid amide potassium salt (4.54 g, Example 1) in DMF
(25 ml) was stirred at rt for 24 h before bulk of the solvent was removed in vacuo.
The residue was treated vwth 10% aq. citric acid. The suspension was filtered, and
the mother liquor was extracted twice with EA. The organic phase was evaporated
and combined with the solid material collected earlier. The crude product was
purified by column chromatography on silica gel eluting with DCM containing 4%
of methanol to give 2-methoxyethanesulfamic acid [6-chloro-5-(4-bromophenyl)-
pyrimidin-4-yll-amide (640 nfig) as a beige foam. LC-MS^: tR = 4.46 min. |M+1]* =
422.93, [M-ir = 420.82.
f) To a suspension of 2-methoxyethanesulfamic acid J6-chloro-5-(4-bromophenyl)-
pyrimidin-4-yll-amide (640 mg g) in ethylene glycol (10 ml) was added potassium
tert.-butylate (1.70 g) in three portions. The resulting clear solution was siiirred for
17 h at gO'C, cooled to rt, diluted with EA (200 ml) and washed unlh 10% aq. citric
acid (150 ml) and water (2x100 ml). The aqueous phase was extracted once more
with EA (100 ml). The combined organic phase was evaporated. The residue was
purified by column chron^tography on silica gel eluting with hexaneiEA 2:1 to 3:1
to give 2-methoxy-ethanesulfamic acid [5-(4-bromophenyl)-6-(2-hydroxyethoxy)-
pyrtmidin-4-yl]-amide (533 mg) as a colourless foam. LC-MS^: tR = 3.81 min,
[M+3(Br isotope)]* = 449.05. [M-1+2(Br isotope)]- = 446.94. 'H-Nt\iR(CDCl3): 3.14-
3.22(m, 2H), 3.30(s. 3H), 3.47-3.53(m, 2H). 3.82-3.88(m, 2H), 4.47-4.52(m. 2H).
5.98-6.06(m br, 1H), 7.l7-7.22(m. 2H). 7.62-7.68(m. 2H), 8.49(s. 1H).
g) NaH (59 mg 55% in mineral oil) was added to a solution of 2-methoxy¬
ethanesulfamic acid t5-(4-bromophenyl)-6-(2-hydroxyethoxy)-pyrimidin-4-y[]-
amide (150 mg) in DMF (4 mi). The mixture was stirred for 5 min before E-bromo-
2-chloropyrimidine (130 mg) was added. The mixture was heated to 5iyc and
stirred for 3 h, diluted with EA (75 ml) and washed with 10% aq. citric acid solution
(50 ml) and water (2x50 ml), The organic phase was evaporated and the residue
was purified by chromatography on prep, tic plates with EA 1 to give 2-methoxy¬
ethanesulfamic acid {5-{4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-
32


2-Methoxy-ethanesulfamic acid {5-(4-broniophenyl)-6-[2-(5-methoxypyrmidin-2-yloxy)-ethoxy]-pyrimidin-4-yl)-amide was obtained in analogy to Example 2 starting from 2-mathoxy-ethanesulfamic acid [5-(4-bromopheriyl)-6-(2-hydroxyethoxy)-pyrimidin-4-yl]-amide (Example 2} and 2-metlianesulfonyl-5-
33

methoxypyrimidine as a white solid. LC-MS^: In = 4.56 min, [M+3(Br isolope)]* = 556.97, lM-1+2(Brisotope)T = 555.05. 'H-NMR(CDCb): 3.14-3.20(m. 2H). 3.28(s. 3H), 3.46-3.51(m. 2H). 3.87(s. 3H), 4.56-4.60{m, 2H). 4.68-4.73(m. 2H). 6.06(s br, 1H), 7.13-7.18(m, 2H), 7.52-7.56(m. 2H), 8.15(s. 2H),8.47(s, 1H).

hydrachliDrothiazide. chlorothiazide, acetolamide, bumetanide, furosemide, metolazone or chlortalidone; sympatholitics like methyldopa, ctonidine, guanabenz, or reserpine; prostacyclin derivatives tike flolan; anti-cholinergic substances and other therapeutics whch serve to treat high blood pressure or any cardiac disorders.
The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given daily in oral form should be betwtien about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg. per adult with a body weight of about 70 kg. The dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which aw adapted to body vueight and age.

WE CLAIM :
1. Sulfamide compounds of the general formula I,

characterized in that
R' represents lower aIkyl-0-(CH2)n-, cycloalkyl-0-(CH2)n-,
cycloalkyl-CH2-0-(CH2)n-;
R^ represents -CH3; R'-Y'{CH2k';
R"* represents ar>'l; heteroaryl;
R* represents hydrogen; trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyioxy; lower
alkyloxy-lower alkyioxy; hydroxy-lower alkyioxy; lower alkyl-sulfinyl; lower alkylthio; lower
alkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyloxy-lower alkyl; hydroxy-lower
alkyloxy-lower alkyl; hydroxy-lower alkyl-amino; lower alkylamino-lower alkyl; amino; di-
lower alkylamino; [N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino; aryl; arylamino; aryl-
lower alkylamino; aryl-thio; aryl-Iower alkylthio; aryloxy; aryl-Iower alkyioxy; aryl-lower
alkyl; arylsulfinyl; heteroaryl; heteroaryl-oxy; heteroary[amino; heteroarylthio; heteroaryl-lower
alkyl; heteroarylsuifmyl; heterocyclyl; heterocyclyl-lower alkyioxy; heterocyclyloxy;

heterocyclylamino; heterocyclyl-lower alkylamino; heterocyciylthio; heterocyclyl-lower alkylthio: heterocyclyl-lower alkyl; heterocyclylsulfmyl; cycloalkyi; cycloalkyloxy; cycloalkyl-lower alkyloxy; cycloalkylamino; cycloalkyl-lower alkylamino; cycloalkylthio; cycloaJkyl-lower alkylthio; cycloalkyl-lower alkyl; cycloalkylsultlnyl;
R* represents hydrogen or methyl;
X represents oxygen; sulfur; -CH2- or a bond;
Y represents a bond, -0-; -NH-; -SO2-NH-; -NH-SOz-NH-; -0-C0-; -C0-0-;
-0-CO-NH-; -NH-CO-0-; -NH-CO-NH-;
n represents the integers 2, 3, or 4;
m represents the integers 2, 3, or 4;
R* represents aryl, heteroaryl, lower alkyl, cycloalkyi, hydrogen;
and optically pure enantiomers, mixtures of enantiomers such as for example racemates, optically pure diastereomers, mixtures of diastercomers, diastereomeric racemates, mixtures of diaslereomeric racemates and the meso-forms and pharmaceutically acceptable salts thereof.
2. The compounds of genera! formula I as claimed in claim 1, wherein R , R , R and R are as defined in general formula 1 in claim I, R^ represents phenyl, mono- or di-substituted phenyl substituted with ethoxy. methoxy or chlorine and X represents oxygen, and pharmaceutically acceptable salts thereof
3. The compounds of general formula I as claimed in claim 1, wherein R', R* and R are as defined in general formula I in claim 1, R"* represents phenyl, mono- or di-subsdtuted phenyl substituted with ethoxy, methoxy or chlorine, X represents oxygen and R represents -(CH;)^,-Y-R^ and pharmaceutically acceptable salts thereof
4. The compounds of general formula I as claimed in claim 1, wherein R', R* and R are as
37

uenneci in general formula I in claim 1, R^ represents phenyl, mono- or di-substituted phenyl substituted with ethoxy. methoxj' or chlorine, X represents oxygen and R^ represents -(CH2)2-0-R\ with R^ being heteroaryl. and pharmaceutically acceptable sahs thereof.


wherein R' , R^ and R* are as defined in general formula I in claim 1 and A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or melhoxy, and pharmaceutically acceptable sahs of compounds of formula III.
7. The compounds as claimed in claim 1, wherein the compounds have the formula IV

wherein R', R** and m are as defined in general formula I in claim 1, A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or methoxy, and R^ represents aryl or heteroaryl, and pharmaceutically acceptable salts of compounds of formula IV.
8. The compounds as claimed in claim 1, wherein the compounds have the formula V


wherein R' is as defined in general formula I in claim 1, A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or methoxy and R^ represents aryl or heteroaryl, and pharmaceutically acceptable salts of compounds of formula V.
9. The compounds of formula V as claimed in claim 8, wherein R is as defined in general formula I in claim I, A represents hydrogen, m.ethyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or methoxy and R represents a substituted pyrimidine, and pharmaceutically acceptable salts of compounds of formula V.
10. The compounds of general formula I as claimed in claim 1, wherein R' represents CH3-O-CH2CH2-, R^ represents hydrogen and R^, R^, and R"* are as defined in general formula I in claim 1. and pharmaceutically acceptable salts of compounds thereof
11. The compounds of formula V as claimed in claim 8, wherein R' represents CHrO-CH2CH2-, A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or
40

methoxy and R-'' represents aryi or heteroaryl, and phannaceutically acceptable salts of compounds of formula V as claimed in claim 8.
12. The compounds of general formula I as claimed in claim 1, wherein the compounds are
selected from the group consisting of:
2-Methoxy-ethanesulfamic acid [6-[2-(5-broino-pyrimidin-2-yloxy)'ethoxy]-5-(2-chioro-5-
methoxy-phenoxy)-pyrimidin-4-ylI-amide;
2'Methoxy-ethanesulfamic acid {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-
ethoxy]-pyrimidin-4-yl}-amide;
2-Methoxy-ethanesulfamic acid {5-(4-bromophenyl)-6-[2-(5-methylsulfanyl-pyrimidin-2-
yioxy)-ethoxy]-pyrimidin-4-yl}-amide; and
2-Methoxy-ethanesulfamic acid {5-(4-bromophenyl)-6-[2-(5-m6thoxypyrimidin-2-yloxy)-
ethoxy] -pyrimi din-4-y 1} -amide.