CA2071193C - Sulfonamides - Google Patents

Sulfonamides

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Publication number
CA2071193C
CA2071193C CA002071193A CA2071193A CA2071193C CA 2071193 C CA2071193 C CA 2071193C CA 002071193 A CA002071193 A CA 002071193A CA 2071193 A CA2071193 A CA 2071193A CA 2071193 C CA2071193 C CA 2071193C
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Prior art keywords
alkyl
methoxy
butyl
alkoxy
phenoxy
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CA2071193A1 (en
Inventor
Kaspar Burri
Martine Clozel
Walter Fischli
Georges Hirth
Bernd-Michael Loffler
Henri Ramuz
Werner Neidhart
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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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
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

The novel sulphonamides of Formula I

(see fig. I) in which the symbols R1-R9, Ra, Rb, X, Y, Z and n have the significance given in the description and salts thereof can be used as active ingredients for the manufacture of medicaments for the treatment of circulatory disorders, especially hypertension, ischemia, vasopasms and angina pectoris.

Description

s The present invention is concerned with novel sulphon-amides and their use as medicaments. In particular, the invention is concerned with novel compounds of the formula R2 Rl R3 ~SO2NH R6 R4 )\\ ~; / R9~ R~
XCH2(CRaRb)nYR5 wherein R1 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl;
R2 signifies hydrogen, halogen, lower-alkoxy, trifluoro-Smethyl or-OCH2COORa; and R3 signifies hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, cycloalkyl, lower-alkoxy or trifluoro-methoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
R4 signifies hydrogen, lower-alkyl, cycloalkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy, lower-alkylsulphinyl, lower-alkylsulphonyl, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenylpropyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl or heterocyclyl;

Grn/7 .5 .92 2 2 ~ 7 ~ 1 9 3 - I
R5 signifies hydrogen, lower-alkyl, lower-alkanoyl, benzoyl, heterocyclylcarbonyl, heterocyclylmethyl or tetrahydro-pyran-2-yl;
R6 to R9 signify hydrogen, halogen, trifluoromethyl, lower-alkyl, s lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkyloxy-carbonyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
0 Z signifies -O-, -S-, vinylene, -CO-, -OCHR10- or -SCHR1 o;
R1 0 signifies hydrogen or lower-alkyl;
X and Y each independently signify O, S or NH; or YR5 also signifies lower-alkylsulphinyl or-OCH2CH(ORC)CH2ORd;
Ral Rb, Rc and Rd each independently signify hydrogen or lower-alkyl; or RCand Rd together signify methylene, ethylene or isopropylidene; and n signifies 1, 2 or 3, and salts thereof.~0 The term "lower" used here denotes groups with 1-7 C atoms, preferably 1-4 C atoms. Alkyl, alkoxy and alkylthio groups as well as alkyl groups as components of alkanoyl groups can be straight-chain or branched. Methyl, ethyl, propyl, 25 isopropyl, butyl, sec. and tert.butyl are examples of such alkyl groups. Halogen denotes fluorine, chlorine, bromine and iodine, with chlorine being preferred. Cycloalkyl residues 3 to 8 C
atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Examples of aryl residues are phenyl and substituted phenyl 30 residues, with halogen, lower-alkyl, lower-alkoxy, carboxyl and trifluoromethyl especially coming into consideration as substituents. Examples of heterocyclyl residues are especially substituted, e.g. by lower alkyl, lower alkoxy, halogen, aryl, aryl-lower alkyl mono- or disubstituted, a unsubstituted mono or 35 bicyclic 5- and 6-membered heterocyclic residues with oxygen, nitrogen or sulphur as the hetero atom, such as 2- and 3-furyl, pyrimidinyl, 2-, 3- and 4-pyridyl and pyridyl N-oxide, 1,2- and 1,4-diazinyl, morpholino, 2- and 3-thienyl, isoxazolyl, oxazolyl, 2~7~ 193 -~

imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl.

The compounds of formula I given above are inhibitors of s endothelin receptors. They can accordingly be used for the treatment of disorders which are associated with endothelin activities, especially circulatory disorders such as hypertension, ischaemia, vasospasms and angina pectoris.

o A preferred group of compounds within formula I comprises those in which Z is -O- and, furthermore, those in which R6 is lower-alkoxy, especially methoxy, and R7, R8 and R9 signify hydrogen; or R6 and R8 signify hydrogen, R7 signifies lower-alkoxy, especially methoxy, and R9 signifies halogen, especially S chlorine.

Preferred substituents R1 and R2 are hydrogen and preferred substituents R3 are lower-alkyl or together with R2 methylene-dioxy. Preferred substituents R4 are hydrogen, 2-pyrimidinyl, 2-20 and 3-furyl, 2- and 3-thienyl, morpholino and p-methoxyphenyl. X
is preferably oxygen. Preferred residues YR5 are hydroxy, lower-alkoxysulphinyl and furoyloxy.

The compounds of formula I can be manufactured by 2s a) reacting a compound of the formula \
R3 ~SO27H R6 N I ~R II

Hal wherein R~, R2, R3, R4 and R6 to R9 and Z have the significance given above and Hal is halogen, with a compound of the formula 4 ' 2~ 7 ~ 19 3 -MX(CH2XCRaRb~nYRS III

wherein X, Y, n, Ra~ Rb and R5 have the significance given s above and M represents an alkali metal, or b) reacting a compound of the formula R3 ~502NH
J~ CHO
~ ~ /

' R4~N~ ~XCH2(CR~Rb)nYRs IV

wherein R1-R5, Ra~ Rb, X, Y and n have the significance given above, with a compound of the formula R8 ~CH2P~(Q)3A V

wherein R6-R9 have the significance given above; Q is aryl and A- is an anion, -20 orc) hydrogenating a compound of the formula R2 Rl R3~SO2NH R6 ~CH=CH~ R7 Vl R4 J~N ~ R9 R8 XCH2(CRaRb)nYR5 wherein R1-R8, Ra, Rb, X, Y and n have the significance given above, S or d) reacting a compound of the formula R2 Rl R3 ~SO2Hal \=/ XIV

with a compound of the formula R4 1\ N / R9~ XV
XCH2(CRaRb)nYRs wherein R1-R9, Ra, Rb, X, Y, Z and n have the significance given above, and, if desired, modifying substituents present in the compound of formula I obtained and/or converting the compound of formula I
obtained into a salt.
The reaction of a compound of formula 11 with a compound of formula 111 is conveniently carried out using the glycol corre-sponding to the compound 111, e.g. in ethylene glycol when n = 2.
The alkali metal M is preferably sodium. The reaction is conveniently carried out while heating, e.g. to 40-120~C. In a preferred embodiment the monosodium salt of ethylene glycol, propylene glycol or butylene glycol is used as the compound of formula lll.
s The reaction of a compound of formula IV with a compound of formula V can be carried out in a manner known per se under the usual conditions of a Wittig reaction. The aryl residue Q is preferably phenyl; examples of anions A- are Cl-. Br-, HSO4- and o tosyloxy. The reaction partners are conveniently reacted with each other in the presence of an acid-binding agent, e.g. in the presence of a strong base such as e.g. butyllithium, sodium hydride or the sodium salt of dimethyl sulphoxide, or K tert.-butylate, but preferably in the presence of an optionally lower 15 alkyl-substituted ethylene oxide such as 1,2-butylene oxide, optionally in a solvent, e.g. in an ether such as diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene, in a temperature range Iying between room temperature and the boiling point of the reaction mixture. In the Wittig reaction 20 interfering reactive groups in the reaction partners, such as carboxyl or amino, are conveniently intermediately protected, e.g.
as a carboxylic acid ester or as the tert.butoxycarbonylamino derivative.

The hydrogenation of a compound of formula Vl can be carried out in a manner known per se for the hydrogenation of olefinic double bonds, e.g. with hydrogen at normal pressure or elevated pressure in the presence of noble metal catalysts such as Pd, especially Pd on carriers such as Pd/C.
Any hydroxy groups and an amino group that may be present in the substituent R4 to R9 of the compound of formula XV are suitably protected when reacting this compound. Hydroxy groups may be protected, e.g., by silyl groups such as dimethyl t-butyl 35 silyl, or acyl groups such as acetyl; and amino groups may be protected by t-butoxy carbonyl a benzyloxy carbonyl. These protecting groups can be inserted and, after the reaction of the compounds XIV and XV, be cleaved by methods known in the art.

Substituents present in the thus-obtained compound of formula I can be modified. For example, a hydroxy group YR5 can be esterified or etherified. A hydroxy group YR5 can be converted s into an ether group, e.g. the tetrahydropyranyl ether, or an ester group, e.g. the acetate, or such groups or ketals, which can be present e.g. as a substituent YR5, contained in the initially obtained reaction product can be cleaved off in a manner known per se. Methylthio groups can be oxidized to methylsulphinyl or o methyl- sulphonyl groups. Furthermore, N-heterocyclic residues such as pyridyl can be oxidized to N-oxides. All of these reactions can be carried out according to methods known per se.
The compounds of formula I can be converted into salts, e.g. alkali salts such as Na and K salts, in a manner known per se.

The compounds which are used as starting materials, insofar as they are not known or their preparation is described hereinafter, can be prepared in analogy to known methods or to the methods described hereinafter.
Compounds of formula 11 can be obtained as illustrated in the following Formula Scheme:

R~, R6 R~ R6 R8~ OH ~COOEt _~ ~COOEt \=~ COOEt \=~ COOEt R9 ~ R9 VII VIII

R4--C . AcOH
NH

Cl R6 R7 ~ R6 N~ ~ HN~O~R7 X IX
R1' R2 H2NSO2 ~R3 II XI

Alkylation of the phenol Vll with diethyl chloromalonate yields compound Vlll which is condensed with formamidine acetate or a homologous compound such as acetamidine acetate to s the pyrimidinedione derivative IX. Using phosphorus oxychloride there is obtained therefrom the dichloro compound X which yields compound 11 upon reaction with a stoichiometric amount of compound Xl. All of these reactions are standard operations and can be carried out under conditions which are usual for such 10 reactions and which are familiar to a person skilled in the art.

Compounds of formula IV can be obtained according to the Reaction Scheme sketched hereinafter:

CH,COOEt 1) R4C(NH)NH2 N~
~ 'COOEt 2) POC13 R4J~N Cl R3 ~SO2NH R3 ~;~SO2NH

N~ N~
R4 J~N X(CH)2YR5 R4 N Cl XIII
oS04/104 IV

.
Condensation of diethyl allyl malonate with formamidine acetate or a R4-substituted derivative followed by replacement of the hydroxy groups by chlorine in the pyrimidinedione obtained yields the dichloropyrimidine Xll which is condensed with a R1, 5 R2, R3-benzenesulphonamide alkali salt with rearrangement of the allyl double bond to the compound Xlll. Reaction of compound Xlll with a compound lll in the manner already described leads to compound XIV. Oxidative cleavage of the double bond of the - propenyl side-chain in compound XIV finally yields the aldehyde IV.

The inhibitory activity of the compounds of formula I on endothelin receptors can be demonstrated using the test procedures described hereinafter:

I: Inhibition of endothelin binding to human placenta membranes (see. Life Sci 44:1429 (1989)) Human placenta is homogenized in 5 mM Tris buffer, pH 7.4, 20 which contains 1 mM MgCI2 and 250 mM sucrose. The homoge-nizate is centrifuged at 4~C and 30009 for 15minutes, the supernatant containing the plasma membrane fraction is centri-fuged with 72000 9 for 30 minutes and the precipitate is washed with 75 mM Tris buffer, pH 7.4, which contains 25 mM
25 MgCI2. Thereafter, precipitate obtained from in each case 10g of original tissue is suspended in 1 ml of 75 mM Tris buffer, pH
7.4, containing 25 mM MgCI2 and 250 mM sucrose, and freeze-dried at -20~C in 1 ml aliquots.

For the binding assay, the freeze-dried membrane prepara-tions are thawed and, after centrifugation at 20~C and 25000 9 for 10 minutes, re-suspended in assay buffer (50 mM Tris buffer, pH 7.4, containing 25 mM MnCI2, 1 mM EDTA and 0.5% of bovine serum albumin). 100 ml of this membrane suspension 3s containing 70 mg of protein are incubated with 50 ml of 1251-endothelin (specific activity 2200 Ci/mMol) in assay buffer (25000 cpm, final concentration 20 pM) and 100 ml of assay buffer containing varying concentrations of test compound. The incubation is carried out at 20~C for 2 hours or at 4~C for 24 hours. The separation of free and membrane-bound radio-ligands is carried out by filtration over a glass fibre filter.

s The inhibitory activity of compounds of formula I
determined in this test procedure is given in Table 1 as the ICsO, i.e. as the concentration [mM] which is required to inhibit 50% of the specific binding of 1251-endothelin.
Table 1 Compound of Example ICso [mM]

0.1 15 2 0.100 6 0.200 1 2 0.125 24 - 0.073 0.050 2 7 0 .099 I l . Inhibition of endothelin-induced contr~ctions in isolated rat ~orta rin~s Rings with a length of 5 mm were cut out from the thorax aorta of adult Wistar-Kyoto rats. The endothelium was removed by lightly rubbing the internal surface. Each ring was immersed at 37~C in 10 ml of Krebs-Henseleit solution in an isolated bath 20 while gassing with 95% O2 and 5% CO2. The isometric stretching of the rings was measured. The rings were stretched to a pre-tension of 3 9. After incubation for 10 minutes with the test compound or vehicle cumulative dosages of endothelin-1 were added. The activity of the test compound was determined by 25 calculating the dosage ratios, i.e. the shift to the right (shift to higher values) of the ECso of endothelin induced by 100 mM of test compound, with ECso denoting the endothelin concentration required for a half-maximum contraction. The greater this dosage ratio is the more potent the test compound is in inhibiting the biological activity of endothelin-1. -The ECso Of endothelin in 5 the absence of test compounds is 0.3 nM.

The thus-obtained values for the shift to the right of the ECsO of endothelin with compounds of formula I are given in Table 2.

Table 2 Compound of Example Dosage ration (Shift to the right) Ill. The inhibitory activity of the compounds of formula I on vasoconstriction can be observed in vivo in rats in the test procedure described hereinafter:

Rats were anaesthetized with Na thiobutabarbital (100 mg/kg i.p.). A catheter for measuring the systemic arterial 20 blood pressure was placed through the femoral artery and a catheter was placed in the vena cava via the femoral vein for injection of the test compounds. A Doppler sonde was placed around the left renal artery and attached to a Doppler measuring apparatus. A renal ischaemia was produced by pinching off the 25 left renal artery at its point of exit for 45 minutes. 10 minutes prior to the induction of the ischaemia he test compounds were administered intraarterially (i.a.) in dosages of 5 mg/kg or intravenously (i.v.) in dosages of 10 mg/kg. In control tests the renal perfusion was reduced by 43 + 4% compared to the pre-ischaemic value.

The results obtained with two compounds of formula I are 5 given in Table 3.

Compound of Example % Decrease in renal perfusion 13.4 + 5.2 6 11.7 + 4.7 On the basis of their capability of inhibiting endothelin binding, the compounds of formula I can be used as medicaments 10 for the treatment of disorders which are associated with vaso-constriction of increasing occurrences. Examples of such dis-orders are high blood pressure, coronary disorders, cardiac insufficiency, renal and myocardial ischaemia, renal insuffici-ency, dialysis, cerebral ischaemia, cardiac infarct, migraine, s subarachnoid haemorrhage, Raynaud syndrome and pulmonary high pressure. They can also be used in atherosclerosis, the preven-tion of restenosis after balloon-induced vascular dilation, inflammations, gastric and duodenal ulcers, ulcus cruris, gram-negative sepsis, shock, glomerulonephtritis, renal colic, 20 glaucoma, asthma, in the therapy and prophylaxis of diabetic complications and complications in the administration of cyclosporin, as well as other disorders associated with endothelin activities.

The compounds of formula I can be administered orally, rectally, parentally, e.g. intravenously, intramuscularly, subcuta-neously, intrathecally or transdermally, or sublingually or as opththalmological preparations, or as an areosol. Capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of application forms.

Intravenous, intramuscular or oral application is a s preferred form of use. The dosages in which the compounds of formula I are administered in effective amounts depend on the nature of the specific active ingredient, the age and the require-ments of the patient and the mode of application. In general, dosages of about 0.1-100 mg/kg body weight per day come into 0 consideration. The preparations containing the compounds of formula I can contain inert or also pharmacodynamically active additives. Tablets or granulates e.g. can contain a series of binders, fillers, carriers or diluents. Liquid preparations can be present, for example, in the form of a sterile water-miscible 15 solution. Capsules can contain a filler or thickener in addition to the active ingredient. Furthermore, flavour-improving additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can 20 also be present.

The previously mentioned carrier materials and diluents can comprise organic or inorganic substances, e.g. water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkyl-25 ene glycols and the like. It is a prerequisite that all adjuvantsused in the manufacture of the preparations are non-toxic.

The following Examples illustrate the invention in more detail. Of the abbreviations used therein THF signifies 30 tetrahydrofuran; DMSO signifies dimethyl sulphoxide; MeOH
signifies methanol; b.p. signifies boiling point; and m.p. signifies melting point.

Example 1 a) 886 mg of p-t-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide were added to a sodium glycolate solution from 3.0 9 of ethylene glycol and 138 mg of sodium. The reaction mixture was stirred at 95~C under argon for 4 hours. Thereafter, the ethylene glycol was distilled off and the residue was partitioned between ethyl acetate and lN hydro-chloric acid. The organic phase was dried and the solvent was 5 distilled off. The residue was crystallized from diisopropyl ether. There were obtained 870 mg of p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzene-sulphonamide. M.p. 143-148~C .

10 b) 775 mg of the previously obtained sulphonamide were dissolved in 20 ml of warm ethanol. The solution was treated with a stoichiometric amount of sodium ethylate, thereafter the ethanol was distilled off until a precipitate formed. 3 ml of isopropyl ether were added to complete the precipitation. There 15 were obtained 775 mg of p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide sodium, m.p. >250~C.

The starting material was prepared as follows:

c) 25 g of guaiacol and 37 9 of dimethyl chloromalonate were added dropwise in succession to a sodium methylate solution from 150 ml of methanol and 4.6 9 of sodium. The suspension was stirred at 45~C for 1 hour with the exclusion of moisture, 25 thereafter the methanol was distilled off. The residue was taken up in 200 ml of toluene and washed with water, 1% sodium hydroxide solution and water until the organic phase was colour-less. After drying and evaporating the solvent the residue was distilied. There were obtained 39.59 of dimethyl (o-methoxy-30 phenoxy)malonate. B.p. 128~C/7 Pa.

d) 5.5 9 of formamidine acetate and 12.7 9 of dimethyl (o-methoxyphenoxy)malonate were added while cooling with ice to a sodium methylate solution from 150 ml of methanol and 3.5 9 of 35 sodium. The reaction mixture was stirred at 0-5~C for 1 hour with the exclusion of moisture, then at room temperature for 2 hours. Thereafter, the solvent was distilled off, the residue was taken up in 100 ml of water, the aqueous phase was extracted with toluene and the organic phases were discarded.
The aqueous phase was acidified, whereby 5-(o-methoxyphenoxy)-6-hydroxy-4(3H)-pyrimidinone separated.

s e) 9.4g of the previously obtained pyrimidinone were suspended in 20 ml of acetonitrile and treated with 12 9 of collidine. Thereafter, 5 ml of POCI3 in 15 ml of acetonitrile were added dropwise with the exclusion of moisture. The reaction mixture was stirred at reflux temperature for 8 hours, 10 thereafter the solvent and excess reagent were distilled off. The residue was taken up in methylene chloride and washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The solution was concen-treated and passed over a short silica gel column with methylene 15 chloride as the elution agent. The eluate was concentrated, the residue was recrystallized from ethanol/hexane. There were obtained 8.5 9 of 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine, m.p. 79-80~C.

20 f) 0.8 g of 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine and 1.5 9 of p-t-butylsulphonamide K in 3 ml of dry dimethyl sulphoxide were heated to 120~C under argon for 1.5 hours.
Thereafter, the dimethyl sulphoxide was distilled off, the residue was partitioned between ethyl acetate and 1 N hydrochloric acid 25 and the organic phase was washed neutral. The organic phase was dried, the solvent was evaporated and the residue was treated with 3 ml of methanol. There were obtained 950 mg of p-t-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzene-sulphonamide, m.p. 152~C.
ExamDle 2 In analogy to Example 1, paragraph a), from p-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulphona-3s mide there was obtained N-[6-(hydroxyethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, m.p.
142-143~C. The compound was converted in analogy to Example 1, paragraph b), in almost quantitative yield into the water-soluble sodium salt.

The starting material was obtained in analogy to Example 1, 5 paragraph f), by reacting 540 mg of 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine and 360 mg of p-isopropylben-zenesulphonamide potassium.
Fxample 3 In analogy to Example 1, paragraph a), from N-[6-chloro-5-(o-tolyloxy)-4-pyrimidinyl]-p-t-butylsulphonamide there was obtained p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-tolyloxy)-4-pyrimidinyl]benzenesulphonamide. M.p. 190-1 92~C .

The starting material was prepared as follows:

Diethyl bromomalonate was converted with sodium o-cresolate into diethyl (o-tolyloxy)malonate, b.p. 1 20~C/7 Pa, in 20 analogy to Example 1, paragraph c).

In analogy to Example 1, paragraph d), from the foregoing malonic ester there was obtained 5-(o-tolyloxy)-6-hydroxy-4(3H)-pyrimidinone from which there was obtained in analogy to 25 Example 1 e) 4,6-dichloro-(o-tolyloxy)pyrimidine, m.p. 78-79~C
(ethanol/hexane). Reaction of the latter compound with p-t-butylsulphonamide potassium finally yielded N-[6-chloro-5-(o-tolyloxy)-4-pyrimidinyl]-p-t-butylsulphonamide.

Example 4 In analogy to Example 1, paragraph a), from p-t-butyl-N-[2-chloro-5-(o,-chlorophenoxy)-4-pyrimidinyl]benzenesulphona-mide there was obtained p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-35 chlorophenyloxy)-4-pyrimidinyl]benzenesulphonamide, m.p. 178-1 79~C (from diisopropyl ether).

The starting material was prepared as follows:

In analogy to Example 1, paragraph e), from diethyl bromo-malonate and sodium o-chlorophenolate there was obtained diethyl (o-chlorophenoxy)malonate as a colourless liquid which 5 was converted in analogy to Example 1, paragraph d), into 5-(o-chlorophenoxy)-6-hydroxy-4(3H)pyrimidinone. From the latter compound there was obtained in analogy to Example 1, paragraph e), 4,6-dichloro-5-(o-chlorophenoxy)pyrimidine, m.p. 76-77~C
(from ethanol/hexane), and from this by reaction with p-t-butyl-10 sulphonamide potassium there was obtained p-t-butyl-N-[2-chloro-5-(o-chlorophenoxy)-4-pyrimidinyl]benzenesulphona-mide, m.p. 186-1 87~C (from methanol).

ExamDle 5 In an analogy to Example 1, paragraph a), from N-[6-chloro-5-(o-chlorophenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulphona-mide there was obtained N-[6-(2-hydroxyethoxy)-5-(o-chloro-phenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, m.p.
20 174-1 75~C (from ethyl acetate).

The starting material was prepared in analogy to Example 1, paragraph f), from 4,6-dichloro-5-(o-chlorophenoxy)pyrimidine and p-isopropylbenzenesulphonamide potassium. M.p. 174-176~C
25 (from methanol).

Example 6 In analogy to Example 1, paragraph a), from p-t-butyl-30 N-[6-chloro-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzene-sulphonamide there was obtained p-t-butyl-N-[6-(2-hydroxy-ethoxy)-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulphona-mide, m.p. 165-1 67~C (from diisopropyl ether).

3s The potassium salt, m.p. 213-215~C, was obtained by reacting the sulphonamide with 0.5N KOH in ethanol.

The sodium salt was prepared in analogy to Example 1, paragraph b). M.p. 265-270~C (from diisopropyl ether).

The starting material was prepared as follows:
s Diethyl bromomalonate was converted with sodium m-methoxyphenolate in analogy to Example 1, paragraph c), into diethyl (m-methoxyphenoxy)malonate, colourless liquid. B.p.
143~C/0.05Torr. The thus-obtained malonic ester was converted 10 in analogy to Example 1, paragraph d), into 5-(m-methoxyphen-oxy)-6-hydroxy-4(3H)-pyrimidinone from which in analogy to Example 1, paragraph e), there was prepared 4,6-dichloro-5-(m-methoxyphenoxy)pyrimidine, m.p. 109-110~C. Reaction of the last-named compound with p-t-butylbenzenesulphonamide S potassium yielded p-t-butyl-N-[6-chloro-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, m.p. 152~C (from meth-anol).

ExamDle 7 In analogy to Example 1, paragraph a), from p-t-butyl-N-[6-chloro-5-phenoxy-4-pyrimidinyl]benzenesulphonamide there was obtained p-t-butyl-N-[6-(2-hydroxyethoxy)-5-phenoxy-4-pyrimi-dinyl]benzenesulphonamide, m.p. 165-167~C (from diisopropyl 25 ether).

The starting material was prepared as follows:

Diethyl bromomalonate was converted with sodium pheno-30 late in analogy to Example 1, paragraph c), into diethyl phenoxy-malonate, b.p. 140~C/0.05Torr. From the malonic ester there was obtained in analogy to Example 1, paragraph e), 5-phenoxy-6-hydroxy-4(3H)pyrimidinone and from this there was obtained in analogy to Example 1, paragraph e), 4,6-dichloro-5-phenoxy-3s pyrimidine, m.p. 89-90~C (from ethanol/hexane). Reaction of the last-named compound with p-t-butylbenzenesulphonamide potas-sium yielded p-t-butyl-N-[6-chloro-5-phenoxy-4-pyrimidinyl]-benzenesulphonamide, m.p. 143-144~C .

F~ample 8 In analogy to Example 1, paragraph a), from 4,6-dichloro-5-s (p-methoxyphenoxy)-4-pyrimidine there was obtained p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenoxy)-4-pyrimidinyl]-benzenesulphonamide, m.p. 141-1 42~C.

The starting material was prepared in analogy to Example 1, paragraph c), d) and e), by reacting diethyl bromomalonate with sodium p-methoxyphenolate to diethyl (p-methoxyphenoxy)malon-ate, b.p. 140~C/7 Pa, and reaction further to 5-(p-methoxy-phenoxy)-6-hydroxy-4(3H)pyrimidinone and, respectively, 4,6-dichloro-5-(p-methoxyphenoxy)-4-pyrimidine, m.p. 107-1 08~C
15 (from ethanol/hexane).

Example 9 In analogy to Example 1, paragraph a), from p-t-butyl-N-[6-20 chloro-5-(o-ethoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide there was obtained p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-ethoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, m.p. 120-121 ~C (from diisopropyl ether).

2s The starting material was prepared from dimethyl chloro-malonate in analogy to Example 1, paragraph c), d), e) and f), via the following intermediates:

Dimethyl (o-ethoxyphenoxy)malonate, b.pt. 1 50~C/7 Pa, 5-(o-ethoxyphenoxy)-6-hydroxy-4(3H)pyrimidinone, 4,6-dichloro-5-(o-ethoxyphenoxy)-4-pyrimidine, 5-p-t-butyl-N-[6-chloro-5-(o-ethoxyphenoxy)-4-pyrimi-dinyl]benzenesulphonamide, m.p. 162-163~C (from methanol).

3s Example 10 In analogy to Example 1, paragraph a), from p-(2,2-dimethylpropyl)-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimi-dinyl]benzenesulphonamide there was obtained p-(2,2-dimethyl-propyl)-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, m.p. 136-137~C (from diiso-propyl ether).

The starting material was prepared in analogy to Example 1, paragraph c), d) and f), via the following intermediates:

p-(2,2-Dimethylpropyl)benzenesulphonyl chloride, b.p.
o 1 05~C/0.005 Torr., 2,2-dimethyl-p-(2,2-dimethylpropyl)benzenesulphonamide potassium, - p-(2,2-dimethylpropyl)-N-[6-chloro-5-(o-methoxyphen-oxy)-4-pyrimidinyl]benzenesulphonamide, m.p. 164-1 65~C (from 15 methanol).

Example 11 In analogy to Example 1, paragraph a), from N-[6-chloro-2-20 methyl-5-(m-methoxyphenoxy)-4-pyrimidinyl]-p-isopropylben-zenesulphonamide, m.p. 152-153~C, there was obtained p-iso-propyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-(m-methoxyphen-oxy)-4-pyrimidinyl]benzenesulphonamide, m.p. 129-1 30~C (from diisopropyl ether).
The starting material was prepared as follows:

In analogy to Example 1, paragraph e), using acetamidine hydrochloride in place of formamidine acetate, dimethyl (m-30 methoxyphenoxy)malonate was converted into 5-(m-methoxy-phenoxy)-2-methyl-6-hydroxy-4(3H)pyrimidinone. Therefrom there was prepared in analogy to Example 1, paragraph e), 4,6-dichloro-2-methyl-5-(m-methoxyphenoxy)pyrimidine and therefrom with p-isopropylbenzenesulphonamide potassium there 3s was prepared N-[6-chloro-2-methyl-5-(m-methoxyphenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, m.p. 152-1 53~C
(from methanol).

F~ample 12 In analogy to Example 1, paragraph a), from N-[6-chloro-5(-(o-methoxy)-2-phenyl-4-pyrimidinyl]-p-isopropylbenzene-5 sulphonamide there was obtained N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]-p-isopropylbenzene-sulphonamide.

- The starting material was prepared in analogy to Example 1, 10 paragraph d), e) and f), from dimethyl (o-methoxyphenoxy)malon-ate via 5-(o-methoxy)-2-phenyl-6-hydroxy-4(3H)-pyrimidinone, 4,6-dichloro-2-phenyl-5-(o-methoxyphenoxy)pyrimidine, m.p.
135-1 36~C, and N-[6-chloro-5-(o-methoxy)-2-phenyl-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, m.p. 190-191 ~C
15 (from methanol).

Example 13 1.3 ml of 1.6M butyllithium in hexane were added at -20~C
2n to 780 mg of benzyltriphenylphosphonium chloride in 10 ml of abs. tetrahydrofuran. The reaction mixture was stirred at -20OC
for 15 minutes and thereafter treated with 280 mg of 2-[(5-formyl-6-p-toluenesulphonamido-4-pyrimidinyl)oxy]ethyl acetate. The reaction mixture was left to warm to room temper-2s ature and was stirred at room temperature for 2 hours. Thetetrahydrofuran was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution, dried and evaporated. The residue was chromatographed over silica gel 30 with methylene chloride/ethyl acetate (9:1 and 8:2). There were obtained 160 mg of 2-[[5-[(E/Z)-styryl]-6-p-toluenesulphon-amido-4-pyrimidinyl]oxy]ethyl acetate, m.p. 146-1 56~C .

The starting material was prepared as follows:
3s From 5-allyl-4,6-dichloropyrimidine-p-toluensulphonamide potassium there was prepared N-[6-chloro-5-[(E/Z)-propenyl]-4-pyrimidinyl]-p-toluenesulphonamide and therefrom by reaction with ethylene glycol sodium there was prepared N-[6-(2-hydroxy-ethoxy)-5-[(E/Z)-propenyl]-4-pyrimidinyl]-p-toluenesulphona-mide, m.p. 130-132~C. Reaction with acetic anhydride in the presence of pyridine in tetrahydrofuran yielded 2-[[5-[(E/Z)-pro-s penyl]-6-p-toluenesulphonamido-4-pyrimidinyl]oxy]ethyl acetate, m.p. 160-1 63~C.

390 mg of the previously named compound and 8 mg of osmium tetroxide were added to a mixture of 2.5 ml of water and 10 7 ml of dioxan and then 450 mg of sodium m-periodate were added at room temperature within 30 minutes and after stirring at room temperature for 2 hours a further 8 mg of osmium - tetroxide were added. The reaction mixture was stirred for a further 5 hours and worked-up, whereby 2-[(5-formyl-6-p-15 toluenesulphonamido-4-pyrimidinyl)oxy]ethyl acetate, m.p. 130-1 44~C (after crystallization from ethyl acetate and diethyl ether), was obtained.

., .~, ,i~,., Example 16 In analogy to Example 15, from 2-[[5-[(E/Z)-styryl]-6-p-10 toluenesulphonamido]-4-pyrimidinyl]oxy]ethyl acetate there was obtained N-[6-(2-hydroxyethoxy)-5-[(E/Z)-styryl]-4-pyrimi-dinyl]-p-toluenesulphonamide as a white resin.

Example 17 In analogy to Example 1, paragraph a), from N-[6-chloro-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-p-isopropylbenzene-sulphonamide and ethylene glycol Na there was obtained N-[6-(2-hydroxyethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-p-20 isopropylbenzenesulphonamide, m.p. 182-183~C (from methylene chloride and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-(2,4,6-trichlorophenoxy)pyrimidine and p-isopropylbenzene-2s sulphonamide, m.p. 217-218~C (from methylene chloride and isopropyl ether).

Fxample 18 In analogy to Example 1, paragraph a), from N-[6-chloro-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-o-toluenesulphonamide and ethylene glycol Na there was obtained N-[6-(2-hydroxy-ethoxy)-6-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-o-toluene-sulphonamide, m.p. 144-145~C (from isopropyl ether).
3s The starting material was prepared from 4,6-dichloro-5-(2,4,6-trichlorophenoxy)-pyrimidine and o-toluenesulphonamide, m.p. 107-109~C (from isopropyl ether).

2s 2071193 Example 19 In analogy to Example 1, paragraph a), from N-[6-chloro-5-5 (2,4,6-trichlorophenoxy)-4-pyrimidinyl]-2,4-xylenesulphonamide and ethylene glycol Na there was obtained N-[6-(2-hydroxy-ethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-2,4-xylene-sulphonamide, m.p. 157-158~C (from isopropyl ether).

The starting material was prepared as follows:

16.9 9 of anhydrous K2CO3 were added to a solution of 18.0 9 of 2,4,6-trichlorophenol and 32.0 9 of diethyl bromo-malonate in 180 ml of acetone and 20 ml of toluene. The S reaction mixture was heated at reflux while stirring for 24 hours, the solution was filtered off from the precipitate and evaporated under reduced pressure. The residue was taken up in toluene, the organic solution was washed with a 5% sodium carbonate solution, then with water, dried over sodium sulphate 20 and, after filtering off the salt under suction, evaporated under reduced pressure. The residue was distilled under < 1 mmHg pressure, whereby there was obtained a colourless oil (b.p. 171-1 74~C) from which with formamidine acetate and sodium methyl-ate there was obtained 5-(2,4,6-trichlorophenoxy)-4,6(3H,5H)-25 pyrimidinedione, m.p. >270~C, which, prior to the further reaction,was dried at 80~C overnight under reduced pressure.

A solution of 7.6 9 of 5-(2,4,6-trichlorophenoxy)-4,6-(3H,5H)-pyrimidinedione, 6.6 9 of tetraethylammonium chloride, 30 3.3 ml of collidine, 13.7 ml of POCI3 in 70 ml of CH3CN was heated at reflux for 4.5 hours, the solution was evaporated under reduced pressure, the residue was treated three times with ether, the combined organic solutions were filtered overnight, evapo-rated under reduced pressure and the residue was recrystallized 3s from ether and n-hexane. There was obtained 4,6-dichloro-5-(2,4,6-trichlorophenoxy)pyrimidine, m.p. 104-1 05~C .

..
From 4,6-dichloro-5-(2,4,6-trichlorophenoxy)pyrimidine and 2,4-xylenesulphonamide there was obtained N-[6-chloro-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-2,4-xylenesulphon-amide, m.p. 267~C (from acetonitrile and isopropyl ether).

ExamDle 20 By reacting 4,6-dichloro-5-[(2-methoxy-4-methyl)phen-oxy]pyrimidine with p-t-butylbenzenesulphonamide and l0 thereafter with ethylene glycol Na there was obtained p-t-butyl-N-[6-(2-hydroxyethoxy)-5-[(2-methoxy-p-tolyl)oxy]-4-pyrimi-dinyl]benzenesulphonamide as a solid.

The starting material was prepared by the reaction of s methylguaiacol with diethyl bomomalonate and thereafter with formamidine acetate to give 5-[(2-methoxy-4-methyl)phenoxy]-4,6(3H, 4H)-pyrimidinedione, m.p. 234-236~C, and further reaction of the latter compound with POCI3.

Example 21 By reacting 4,6-dichloro-5-[(2-methoxy-4-methyl)phen-oxy]pyrimidine with p-isopropylbenzenesulphonamide and thereafter with ethylene glycol Na there was obtained N-[5-(2-methoxy-4-methyl)phenoxy]-6- (2-hydroxyethoxy) -4-pyrimidinyl]-p-isopropylbenzene- sulphonamide, m.p. 135-136~C (from ethyl acetate).
Example 22 By reacting 4,6-dichloro-5-[(2-methoxy-4-methyl)phen-oxy]pyrimidine with o-ethylbenzenesulphonamide and thereafter with ethylene glycol Na there was obtained N-[5-(2-methoxy-4-methyl)phenoxy-6-(2-hydroxyethoxy)-4-pyrimidinyl]-o-ethyl-benzenesulphonamide as a solid.
3s D

Fxample 23 By reacting 4,6-dichloro-5-(2-methoxy)phenoxy-2-methyl-pyrimidine with p-tert-butylphenylsulphonamide and thereafter s with ethylene glycol Na there was obtained p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulphonamide, m.p. 123-124~C (from ethyl acetate).

Example 24 By reacting 4,6-dichloro-5-(2-methoxy)phenoxy-2-methyl-pyrimidine with p-isopropylbenzenesulphonamide and thereafter with ethylene glycol Na there was obtained N-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl)-p-15 isopropylbenzenesulphonamide, m.p. 124-1 26~C (from acetoni-trile, isopropanol and water).

ExamDle 25 By reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2-tri-fluoromethylpyrimidine with p-isopropylbenzenesulphonamide and thereafter with ethylene glycol Na there was obtained N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-trifl uoromethyl)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide as a solid.

Example 26 By reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2-tri-fluoromethylpyrimidine with p-tert-butylbenzenesulphonamide 30 and with ethylene glycol Na there was obtained p-tert-butyl-N-[6-(2-hydroxyethoxy)-5(o-methoxyphenoxy)-2-(trifluoromethyl)-4-pyrimidinyl]benzenesulphonamide, m.p. 190-1 92~C (from toluene). Sodium salt: M.p. 288-289~C.

3s Example 27 By reacting 5-(1,3-benzodioxol-5-yloxy)-4,6-dichloro-pyrimidine with p-tert-butylphenylsulphonamide and thereafter with ethylene glycol Na there was obtained N-[5-(1,3-benzo-dioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-tert-butylbenzenesulphonamide as a solid.

ExamDle 28 By reacting 5-(1,3-benzodioxol-5-yloxy)-4,6-dichloro-pyrimidine with p-isopropylbenzenesulphonamide and thereafter with ethylene glycol Na there was obtained N-[5-(1,3-benzo-10 dioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-iso-propylbenzenesulphonamide as a solid.

Example 29 By reacting 5-(2-methoxyphenoxy)-4,6-dichloropyrimidine with o-methoxyphenylsulphonamide and thereafter with ethylene glycol Na there was obtained N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-o-methoxybenzenesulphonamide, m.p. 164-1 65~C (from ethyl acetate).
ExamDle 30 By reacting p-tert-butyl-N-[6-chloro-5-(o-methoxy-phenoxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide with the 25 monosodium salt of 1,4-butanediol there was obtained p-tert-butyl-N-[6-(4-hydroxybutoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide as a white foam.

ExamDle 31 By reacting 4,6-dichloro-5-(2-naphthyloxy)pyrimidine with p-isopropylphenylsulphonamide and thereafter with the sodium salt of ethylene glycol there was obtained N-[6-(2-hydroxy-ethoxy)-5-(2-naphthyloxy)-4-pyrimidinyl]-p-isopropylbenzene-3s sulphonamide, m.p. 160-161~C (from isopropyl ether).

Example 32 By reacting 4,6-dichloro-5-t2-naphthyloxy)pyrimidine with p-tert-butylphenylsulphonamide and thereafter with ethylene s glycol Na there was obtained N-[6-(2-hydroxyethoxy)-5-(2-naphthyloxy)-4-pyrimidinyl]-p-tert-butylbenzenesulphonamide, m.p.197-1 98~C (from isopropyl ether).

Example 33 By reacting 4,6-dichloro-5-(o-methoxyphenoxy)-2-propyl-pyrimidine with p-isopropylphenylsulphonamide and thereafter with ethylene glycol Na there was obtained N-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]-p-iso-15 propylbenzenesulphonamide as a solid.

Example 34 By reacting 4,6-dichloro-5-(o-methoxyphenoxy)-2-propyl-20 pyrimidine with p-tert-butylphenylsulphonamide and thereafter with ethylene glycol Na there was obtained p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]-benzenesulphonamide.

Exam~le 35 By reacting 4,6-dichloro-5-(o-methoxy)phenoxy-2-methyl-pyrimidine with a,~,a-trifluoro-p-toluenesulphonamide and thereafter with ethylene glycol Na there was obtained oc,a,oc-30 trifluoro-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-toluenesulphonamide, m.p. 144-1 45~C
(from ethyl acetate).

ExamDle 36 By reacting 4,6-dichloro-5-(o-methoxy)phenoxy-2-methyl-pyrimidine with p-chlorophenylsulphonamide and thereafter with ethylene glycol Na there was obtained p-chloro-N-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzene-sulphonamide, m.p. 134-135~C (from ethyl acetate).

Example 37 s By reacting 4,6-dichloro-5-(o-methoxy)phenoxy-2-methyl-pyrimidine with p-(trifluoromethoxy)benzenesulphonamide and thereafter with ethylene glycol Na there was obtained N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-o p-(trifluoromethoxy)benzenesulphonamide, m.p. 138-1 40~C (from ethyl acetate).

Example 38 S By reacting 4,6-dichloro-5-(o-methoxy)phenoxy-2-methyl-pyrimidine with o-ethylbenzenesulphonamide and thereafter with ethylene glycol Na there was obtained o-ethyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzenesulphonamide as a white foam.
Example 39 By reacting 4,6-dichloro-5-(o-methoxy)phenoxy-2-methyl-pyrimidine with p-toluenesulphonamide thereafter with ethylene 25 glycol Na there was obtained N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-toluene-sulphonamide as a white foam.

Example 40 By reacting 4,6-dichloro-5-(o-methoxy)phenoxy-2-methylpyrimidine with 2-naphthylsulphonamide and thereafter with ethylene glycol Na there was obtained N-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-35 naphthylsulphonamide as a foam.

-ExamDle 41 By reacting p-tert-butyl-N-[6-chloro-5-(o-methoxyphen-oxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide with the s monosodium salt of 1,3-propanediol there was obtained p-tert-butyl-N-[6-(3-hydroxypropoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide as a white foam.

Example 42 In analogy to Example 1, paragraph a), 300 mg of p-t-butyl-N-[6-chloro-5-[(o-methylthio)phenoxy]-4-pyrimidinyl]benzene-sulphonamide were converted into N-[6-(2-hydroxyethoxy)-5-[(o-methylthio)phenoxy]-4-pyrimidinyl]benzenesulphonamide. There 15 were obtained 250 mg of p-t-butyl-N-[6-(2-hydroxyethoxy)-5-[(o-methylthio)phenoxy]-4-pyrimidinyl]benzenesulphonamide, m.p.
1 49-1 50~C.

The starting material was prepared as follows:
a) Dimethyl (o-methylthio)phenoxymalonate was obtained from dimethyl chloromalonate and (o-methylthio)phenol in analogy to Example 1, paragraph c). From 17 9 of (o-methylthio)phenol there were obtained 23 9 of malonate from toluene-hexane.

b) 9.15 g of 5-[(o-methylthio)phenoxy]-6-hydroxy-4-(3H)-pyrimidinone, MS:250 (M), were obtained from 13.5g of the malonate from a) and formamidine acetate in analogy to Example 1, paragraph d).
c) 2.5 g of this compound and 2.9 9 of diisopropylethylamine were suspended in 15 ml of acetonitrile. 2 ml of POCI3 were added dropwise to the suspensior~ and the mixture was subse-quently boiled at reflux for 5 hours. 4,6-Dichloro-5-[(o-methyl-35 thio)phenoxy]pyrimidine was obtained after working-up in analogy to Example 1, paragraph e). After crystallization from n-hexane there was obtained 1 g of pyrimidine derivative, m.p. 89-90~C.

d) In analogy to Example 1, paragraph f), 580 mg of 4,6-dichloro-5-[(o-methylthio)phenoxy]pyrimidine were converted with 850 mg of p-t-butylbenzenesulphonamide K into p-t-butyl-N-[6-chloro-5-[(o-methylthio)phenoxy]-4-pyrimidinyl]benzene-s sulphonamide. After crystallization from MeOH there wereobtained 480 mg of white crystals, m.p. 154-155~C.

Example 43 10 a) In analogy to Example 1, paragraph a), 350 mg of p-t-butyl-N-[(6-chloro-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]-benzenesulphonamide were converted into p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]-benzenesulphonamide. After crystallization from diisopropyl s ether there were obtained 330 mg of white crystals, m.p. 160-161~C.

b) 225 mg of this compound were dissolved in EtOH. The stoichiometric amount of KOH in MeOH was added to the solution.
20 Then, the solvent was distilled off and diisopropyl ether was added to the residue, whereby there was obtained p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimi-dinyl]benzenesulphonamide potassium, MS: 588 [(M + K)+].

2s Example 44 In analogy to Example 1, paragraph a), from N-[2-amino-6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-p-tert.-butylben-zenesulphonamide there was obtained N-[2-amino-6-(2-hydroxy-3~ ethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-p-tert.-butyl-benzenesulphonamide, white crystals of melting point 168~C
(from diisopropyl ether).

The starting material was prepared as follows:
3s a) 7.65 9 of dimethyl (5-o-methoxy)phenoxymalonate and 3 9 of guanidine hydrochloride were added to a solution of 2.3 9 of Na in 100 ml of methanol. The suspension was stirred at room temperature under argon for 3 hours. Then, the methanol was distilled off and the residue was taken up in H2O. After the usual treatment, as already described, the compound was precipitated by the dropwise addition of acetic acid until the pH of the 5 solution had reached 4.5. There were obtained 6.4 g of crude product of which 1.359 were suspended in 10ml of dioxan.
1.4 9 of N-ethyldiisopropylamine, 2 ml of POCI3 and 1 9 of triethylbenzylammonium chloride were added thereto in succes-sion. The mixture was boiled at reflux under an argon atmosphere 10 while stirring vigorously. After 30 minutes the solvent mixture was distilled off, the residue was taken up in ethyl acetate and extracted with H2O and saturated NaHCO3 solution. Purification - was carried out by chromatography on silica gel (CH2CI2-ethyl acetate, 9:1 vol., as the eluent). There was obtained 2-amino-15 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine as a colourless solid. M.p. 190~C.

b) 0.5 9 of the foregoing dichloro compound and 0.75 9 of p-tert.-butylbenzenesulphonamide Na in 2 ml of DMSO were 20 converted at 90~C into N-[2-amino-6-chloro-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-p-tert-butylbenzenesulphonamide, m.p.
1 94-1 95~C
Example 45 a) In analogy to Example 1, paragraph a), 478 mg of p-tert-butyl-N-[6-chloro-2-methyl-5-[o-(methylthio)phenoxy]pyrimi-dinyl]benzenesulphonamide and Na glycolate in ethylene glycol were converted into p-tert-butyl-N-[6-(2-hydroxyethoxy)-2-30 methyl-5-[o-(methylthio)phenoxy]-4-pyrimidinyl]benzene-sulphonamide, m.p. 166-1 67~C.

b) 225 mg of this compound were converted into the sulphon-amide salt by adding the stoichiometric amount of aqueous NaOH.
3s Then, it was diluted with methanol to give a homogeneous solution. 100 mg of NalO4 dissolved in 2 ml of H2O were added to this solution and the mixture was stirred at room temperature for 8 hours. Then, it was evaporated to dryness. The residue was partitioned between ethyl acetate and aqueous 0.1N H2SO4. After evaporating the organic phase the p-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-methyl-5-[o-(R,S-methylsulphinyl)phenoxy]-4-pyrimidinyl]benzenesulphonamide was crystallized from diiso-s propyl ether. 150mg of white crystals were obtained. MS: m/e =520 (M+H)+.

g The starting material was prepared as follows:

5.4 9 of dimethyl (o-methylthiophenoxy)malonate and 2.1 9 of acetamidine hydrochloride were converted into 6-hydroxy-2-methyl-5-[o-(methylthio)phenoxy]-4(3H)-pyrimidine and this was converted into 4,6-dichloro-2-methyl-5-[o-(methylthiophenoxy)-pyrimidine, m.p. 132-1 33~C .
0.9 9 of the foregoing dichloro compound and 1.3 9 of p-tert-butylbenzenesulphonamide K were converted into p-tert-butyl-N-[6-chloro-2-methyl-5-[o-methylthio)phenoxy]-4-pyrimi-dinyl]benzenesulphonamide. M.p. 162-1 63~C .
Exam~le 46 1.22 9 of (S)-1,2-di-O-isopropylidene-glycerol were added dropwise under an argon atmosphere to a suspension of 170 mg 2s of NaH in 2 ml of dry THF. Subsequently, 1.03 g of p-tert-butyl-N- [6-chloro-5 -(o-methoxyphenoxy)-2-(p-methoxyphenyl)-4-pyrimidinyl]benzenesulphonamide and 2 ml of DMSO were added.
The mixture was left to react at 95~C for 4 hours, whereby the THF distilled off. Then, 0.5 ml of H2O was added and the solvent 30 mixture and the excess reagent were distilled off under reduced pressure. The residue was taken up in 20 ml of dioxan; 1 ml of aqueous 1 N HCl was added and the mixture was left to react at 65~C for 45 minutes. The mixture was then evaporated to dryness. The residue was partitioned between ethyl acetate and 3 5 1 N hydrochloric acid. After the usual working-up the compound was purified on silica gel with ethyl acetate as the eluent. There was obtained 0.98 g of (S)-4-tert-butyl-N-[6-(2,3-dihydroxy-propyloxy)-5 -(o-methoxy-phenoxy)-2-(p-methoxyphenyl)-pyrimidin-4-yl] -benzenesulphonamide, m.p. 141 - 142~C (from diethyl ether).

The starting material was prepared as follows:

In analogy to Example 1, paragraph d), 7.63 g of dimethyl (o-methoxyphenoxy)malonate and 5,6 g of p-methoxy-benz-amidine hydrochloride were condensed to give 2-(p-methoxy-phenyl)-5 -(o-methoxyphenoxy)-6-hydroxy-4(3H)-pyrimidinone.
0 Reaction of this compound in analogy to Example 1, paragraph e), yielded 4,6-dichloro-2-(p-methoxyphenyl)-5-(o-methoxy-phenoxy)-pyrimidine, m.p. 113-114~C, from which in analogy to Example 1, paragraph f), there was obtained p-tert-butyl-N-[6-chloro-5 -(o-methoxyphenoxy)-2-(p-methoxyphenyl)-4-pyrimi-5 dinyl]benzenesulphonamide, m.p. 221 -222~C.

Example 47 210 mg of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-20 phenoxy)-2-ethyl-6-(2-methylsulphanyl-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide were dissolved in 5 ml of MeOH and 0.2 ml of IN NaOH. 95 mg of NaIO4 dissolved in 0.5 ml of H2O
were added thereto and the mixture was stirred at room temperature for 5 hours, whereby a suspension resulted. Then, 2s 0.2 ml of lN HCl was added and the mixture was subsequently evaporated to dryness. The residue was partitioned between ethyl acetate and 0. lN HCl and worked-up as usual. For purification, the compound was chromatographed on silica gel using ethyl acetate-MeOH (6: 1 by vol.) as the eluent. There were 30 obtained 160 mg of (RS)-4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-ethyl -6-(2-methylsulphinyl-ethoxy)-pyrimidin-4-yl] -benzenesulphonamide as a white powder. MS: 581 (M).

The starting material was prepared as follows:
In analogy to Example 1, paragraph c), from 2-chloro-5-methoxy-phenol and dimethyl chloromalonate there was obtained dimethyl (2-chloro-5-methoxy-phenoxy)malonate, m.p. 68-69~C.

Condensation with propanidine hydrochloride yielded 2-ethyl-5-(2-chloro-5-methoxy-phenoxy)-6-hydroxy-4(3H)-pyrimidinone from which in analogy to Example 1, paragraph e), there was obtained 4,6-dichloro-2-ethyl-5-(2-chloro-5-methoxy-phenoxy)-5 pyrimdine, m.p. 113-113.5~C. This compound was converted analogously to Example 1, paragraph f), into 4-tert-butyl-N-[6-chloro-S -(2-chloro-5-methoxy-phenoxy)-2-ethyl-pyrimidin-4-yl]-benzenesulphonamide, m.p. 142-143~C (from ethanol).

o 300 mg of 2-(methylthio)ethanol were added dropwise under argon to a suspension of 63 mg of NaH in dry THF.
Subsequently, 300 mg of the previously obtained sulphonamide and 1 ml of 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone were added thereto. The mixture was left to react at 80~C for 1S 3 hours. After the usual working-up of the reaction mixture and purification on silica gel (CH2CI2-diethyl ether, 95/5 vol, as the eluent) there were obtained 160 mg of 4-tert-butyl-N-[5-(2-chloro-S -methoxy-phenoxy)-2-ethyl-6-(2-methylsulphanyl-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide as a white 20 powder.
Example 48 a) In analogy to Example 1, from 4-tert-butyl-N-[6-chloro-5-~ 25 (2-chloro-5-methoxy-phenoxy)-2-methylpyrimidine-4-yl]-benzenesulphonamide there were manufactured 4-tert-butyl-N-[5 -(2-chloro-5 -methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide. From 500 mg of the starting material there were obtained 430 mg of white 30 crystals. M.p. 141-141.5~C (from isopropyl ether).

b) 140 mg of the compound obtained were esterified with 3-furancarboxylic acid under the following conditions: 140 mg of the previously obtained sulphonamide, 170 mg of N-ethyl-N'-(3-3s dimethylaminopropyl)-carbodiimide hydrochloride, 170 mg of Et3N and S mg of dimethylamino pyridine were dissolved in 2 ml of dichloromethane and the solution was left to stand at room temperature for 24 hours. Then, S ml of THF and 1 ml of 21~7119~

H2O were added thereto and the solution was stirred for 30 minutes. Subsequently, it was evaporated to dryness. The residue was partitioned between dichloromethane and lN HCl, then washed three times with H2O and isolated as usual. The s compound was purified on silica gel using dichloromethane-diethyl ether (95:5 by vol.) as the eluent. There were obtained 120 mg of 4-tert-butyl-N-[5-(2-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-(2-(3 -furoyloxy)ethoxy)-2-methyl-pyrimidin-4-yl] -benzenesulphonamide .
The starting material was prepared as follows:

In analogy to Example 1, paragraph d), dimethyl (2-chloro-5-methoxy-phenoxy)malonate was condensed with acetamidine l s hydrochloride to give (2-chloro-5 -methoxy-phenoxy)-2-methyl-6-hydroxy-4(3H)-pyrimidinone. Therefrom in analogy to Example 1, paragraph e), there was obtained 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-2-methyl-pyrimidine, m.p. 125- 130~C, and therefrom in analogy to Example 1, paragraph f), there was 20 obtained 4-tert-butyl-N-[6-chloro-5-(2-chloro-5-methoxy-phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide, m.p.
182~C (from MeOH).

Example 49 2s In analogy to Example 47, 90 mg of N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-methylsulphanyl-ethoxy)-pyrimidin-4-yl]-1,3-benzodioxol-5-sulphonamide were oxidized with NaIO4 to give (RS)-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-methyl-30 sulphinyl-ethoxy)-pyrimidin-4-yl] - 1,3 -benzodioxol-5-sulphon-amide. There were obtained 65 mg of white powder. MS: 542.1 (M+H+).

The starting material was prepared as follows:
3s In analogy to Example 1, paragraph d), dimethyl (2-chloro-5-methoxy-phenoxy)malonate was condensed with formamidine acetate to give (2-chloro-5-methoxy-phenoxy)-6-hydroxy-4(3H)-pyrimidinone. Therefrom in analogy to Example 1, paragraph e),there was obtained 4,6-dichloro-5-(2-chloro-2-methoxy-phenoxy)-pyrimidine, m.p. 88-89~C (from ethanol).

s Reaction of 611 mg of 4,6-dichloro-5-(2-chloro-2-methoxy-phenoxy)-pyrimidine with 813 mg of 1,3-benzodioxol-5-sulphonamide K yielded 535 mg of N-[6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin -4-yl] -1 ,3 -benzodioxol -5 -sulphonamide. The last-named compound was converted into N-0 [5-(2-chloro-5-methoxy-phenoxy)-6-(2-methylsulphanyl-ethoxy)-pyrimidin-4-yl]-1,3-benzodioxol-5-sulphonamide as described in the preparation of the starting material in Example 47 .
ExamDIe 50 A solution of 0.11 9 of sodium in 3.0 ml of ethylene glycol was heated to 110~C with 0.265 g of 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophen)-2-yl-pyrimidin -4-yl] -20 benzenesulphonamide, cooled for a further 4 hours, poured on toice and adjusted to pH 3 with lM tartaric acid. The suspension obtained was extracted with ethyl acetate, the organic extracts were combined, washed with water, dried with sodium sulphate and concentrated under reduced pressure. The residue was 2s chromatographed on silica gel with CH2Cl2-ethyl acetate 9:1 and yielded 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl] -benzenesulphon-amide as a white foam. MS: M+ = 555.
The starting material was prepared as follows:

a) A solution of 5.17 g of Na in 200 ml of abs. methanol was treated with 21.15 g of diethyl (o-methoxyphenoxy)malonate and 16.2 g of thiophene-2-carboxamidine hydrochloride and the 3s suspension was stirred at room temperature overnight and evaporated under reduced pressure. The residue was taken up in lN NaOH, the ~lk~line solution was acidified with lN HCl, the precipitate was filtered off under suction, washed thoroughly with water and dried in a high vacuum at 80~C. The 5-(o-methoxyphenoxy)-2-(2-thienyl)-4,6-dihydroxy-pyrimidine of m.p. >250~C (dec.) was used in the next step without further purification .
s b) A suspension of 4.6 g of 5-(o-methoxyphenoxy)-2-(2-thienyl)-4,6-dihydroxy-pyrimidine, 4.7 ml of N,N-diisopropyl-N-ethylamine and 6.4 g of PCls was boiled at reflux for 20 hours.
The mixture was then evaporated under reduced pressure and the o residue was poured on to ice and extracted with ethyl acetate.
The combined extracts were washed with water, dried and evaporated in a vacuum. The residue was chromatographed on silica gel with toluene and yielded 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidine, m.p. 118-120~C.
1s c) A solution of 0.353 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidine in 5 ml of DMSO was heated to 150~C with 0.376 g of p-tert-butylbenzenesulphon-amide for 30 minutes. The solution was concentrated in a high 20 vacuum and the oily residue was poured on to ice, made acid (pH = 3) and the suspension was extracted with ethyl acetate.
The organic extracts were combined, washed with water, dried over sodium sulphate and concentrated under reduced pressure.
The residue was chromatographed on silica gel with toluene-ethyl 2s acetate 9:1 and yielded 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl] -benzenesulphon-amide as a white foam.

Example 5 1 In an analogous manner to Example 50, from 4-tert-butyl-N- [6-chloro-5 -(2-methoxy-phenoxy)-2-(thiophen-3 -yl)-pyrimidin-4-yl]-benzenesulphonamide and ethylene glycol Na there was obtained 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-3s methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzene-sulphonamide, m.p. 152-153~C (from toluene).

The 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulphonamide (foam) was prepared starting from thiophene-3-carboxamidine hydro-chloride via rac-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-5 3,4,5,6-tetrahydro-pyrimidine-4,6-dione (solid of m.p. ~250~C) and 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidine (m.p. 98-99~C).

Example 52 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-2-(furan -2-yl)-5 -(2-methoxy-phenoxy)-pyrimidinyl-4-yl] -benzene-sulphonamide and ethylene glycol Na there was obtained 4-tert-butyl -N- [2-(furan-2-yl)-6-(2-hydroxy -ethoxy)-5 -(2 -methoxy-5 phenoxy)-pyrimidin-4-yl]-benzenesulphonamide as an amorphous solid.

The 4-tert-butyl-N-[6-chloro-2-(furan-2-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide (foam) was 20 prepared starting from furan-2-carboxamidine hydrochloride via rac-2-(furan-2-yl)-5 -(2-methoxy -phenoxy) -pyrimidine-4,6-dione (solid with a decomposition point of 255-258~C) and 4,6-dichloro-2-(furan-2-yl)-5-(2-methoxy-phenoxy)-pyrimidine.

Example 53 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-2-furan-3 -yl-5 -(2-methoxy-phenoxy)-pyrimidin -4-yl] -benzene-sulphonamide and ethylene glycol Na there was obtained 4-tert-30 butyl-N-[2-(furan-3-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide as a solid of m.p.
120-1 22OC (from toluene/n-hexane).

The 4-tert-butyl-N-[6-chloro-2-(furan-3-yl)-5-(2-methoxy-35 phenoxy)-pyrimidin-4-yl]-benzenesulphonamide (foam) was prepared starting from furan-3-carboxamidine hydro- chloride via rac-2-(furan-3-yl)-5 -(2-methoxy-phenoxy)-4,6-dioxo- 1,4,5,6-tetrahydro-pyrimidine (solid with a m.p. of more than 300~C with -decomposition) and 4,6-dichloro-2-(furan-3-yl)-5-(2-methoxy-phenoxy)-pyrimidine.

Example 54 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidin-4-yl] -benzenesulphonamide and ethylene glycol Na there was obtained 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-1 o 2-(pyridin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide as a solid with a m.p. above 250~C (from ethyl acetate).

The 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide (m.p. 197-5 198~C from isopropyl ether) was prepared starting from pyridine-2-carboxamidine hydrochloride via 5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)pyrimidine-4,6-diol and 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidine, m.p. 122- 123 ~C .

Example-55 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-(2 -methoxy -phenoxy)-2-(pyridin -4-yl)-pyrimidin-4-yl] -benzenesulphonamide and ethylene glycol Na there was obtained 25 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide as a solid of m.p. 166-167~C from acetone-ether.

The 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-30 (pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide potassium (1: 1), m.p. 193 - 196~C from H2O, was prepared starting from pyridine-4-carboxamidine hydrochloride via 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol and 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine, m.p. 173-3s 176~C.

Example 56 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-(2-methoxy -phenoxy)-2-(pyridin-3 -yl)-pyrimidin-4-yl] -s benzenesulphonamide and ethylene glycol Na there was obtained4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5 -(2-methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidin-4-yl]-benzenesulphonamide K as a foam. MS: (M+H)+ = 551.2.

lo The 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidin-4-yl]-benzenesulphonamide was prepared starting from pyridine-3-carboxamidine hydrochloride via rac-5 -(2-methoxy-phenoxy)-2-(pyridin-3 -yl)-tetrahydro- 1 H-pyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxy-phenoxy)-5 2-(pyridin-3 -yl)-pyrimidine (m .p. 164- 165 ~C) .

Example 57 A suspension of 525 mg of 4-tert-butyl-N-[6-chloro-5-(2-20 methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidin-4-yl)benzene-sulphonamide in 1 ml of glacial acetic acid was treated with 2.5 ml of 40~o peracetic acid and slowly heated to reflux. After 2 minutes the mixture was cooled, evaporated under reduced pressure and the residue was recrystallized from ethyl acetate.
2s There was obtained 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide of m.p. 201-202~C (with decomposition).

ExamDIe 58 216 mg of 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine l-oxide were added to a solution of 46 mg of Na in pure ethylene glycol and the solution which slowly resulted was heated at 80~C
3 s overnight. The solution was poured into aqueous acetic acid, the precipitate was extracted with ethyl acetate, triturated with ether and filtered off under suction. There was obtained 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5 -(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine l-oxide as an amorphous mass which was dried in a high vacuum at 40~C. MS:
(M+H)+ = 567.4.

Example 59 In analogy to Example 57, from 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidinyl-4-yl] -benzenesulphonamide and peracetic acid there was obtained 4-[4-0 (4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine l-oxide, m.p. 247-249~C (from CH2C12 and isopropyl ether).

Example 60 In analogy to Example 58, from 4-[4-(4-tert-butyl-phenyl-sulphonylamino)-6-chloro-5 -(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine l-oxide and Na ethylene glycolate in ethylene glycol there was obtained 4-[4-(4-tert-butyl-phenylsulphonylamino)-6-20 (2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]
pyridine l-oxide as an amorphous mass. MS: (M+H)+ = 567.4, (M+Na)+ = 589.4.

Example 6 1 2s In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-2-(2-methoxy-ethyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl] -benzenesulphonamide and ethylene glycol Na there was obtained 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-[2-(hydroxy-ethoxy)-30 ethyl]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamide. MS: M+ = 562. The corresponding sodium salt (prepared according to usual methods) is a white solid which was dried in a high vacuum.

3s The 4-tert-butyl-N-[6-chloro-2-(2-methoxy-ethyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl-benzenesulphonamide was prepared starting from methoxy-propionamidine hydrochloride via 2-(2-methoxy-ethyl)-5-(o-methoxyphenoxy)-4,6-( 1 H,5H)-pyrimidinedione and 4,6-dichloro-2-(2-methoxy-ethyl)-5-(2-methoxy-phenoxy)-pyrimidine.

Example 62 s In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-2-cyclopropyl -5 -(2-methoxy-phenoxy)-pyrimidin-4-yl] -benzene-sulphonamide and ethylene glycol Na there was obtained 4-tert-butyl-N- [2-cyclopropyl-6 -(2-hydroxy-ethoxy)-5 -(2-methoxy-o phenoxy)-pyrimidin-4-yl]-benzenesulphonamide as a foam. MS:
M+ = 513.

The 4-tert-butyl-N-[6-chloro-2-cyclopropyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide was prepared s starting from cyclopropyl-formamidine hydrochloride via rac-2-cyclopropyl -5 -(2-methoxy-phenoxy)- 1 H-pyrimidine-4,6-dione (m.p. 243-244~C) and 4,6-dichloro-2-cyclopropyl-5-(2-methoxy-phenoxy)pyrimidine (m.p. 80-82~C).

Example 63 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-2-ethyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl] -benzene-sulphonamide and ethylene glycol Na there was obtained 4-tert-2s butyl-N-[2-ethyl-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide as a foam.

The 4-tert-butyl-N-[6-chloro-2-ethyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide was prepared 30 starting from propionamidine hydrochloride via rac-2-ethyl-5-(2-methoxy-phenoxy)-lH-pyrimidine-4,6-dione (m.p. 265~C with decomposition) and 4,6-dichloro-2-ethyl-5-(2-methoxy-phenoxy)-pyrimidine (m.p. 70-71 ~C).

3s Example 64 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-2-isopropyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl] -benzenesulphonamide and ethylene glycol Na there was obtained4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-isopropyl-S -(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide as a solid.
s The 4-tert-butyl-N-[6-chloro-2-isopropyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide was prepared starting from isopropionamidine hydrochloride via rac-2-iso-propyl -5 -(2-methoxy-phenoxy)- 1,4,5,6-tetrahydro-pyrimidine-o 4,6-dione and 4,6-dichloro-2-isopropyl-5-(2-methoxy-phenoxy)-pyrimidine (m.p. 70-72~C).

- Example 65 1 S In analogy to Example S0, from 4-chloro-N-[6-chloro-5-(5-fluoro-2-methoxy -phenoxy)-pyrimidin-4-yl] -benzenesulphon-amide and ethylene glycol Na there was obtained 4-chloro-N-[3-(5 -fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin -4-yl]-benzenesulphonamide, m.p. 152-154~C (from CH3CN and iso-20 propyl ether).

The 4-chloro-N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidin -4-yl] -benzenesulphonamide (m.p. 169- 171 ~C) was prepared from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-25 pyrimidine and 4-chlorobenzenesulphonamide K.

Example 66 In analogy to Example 50, from N-[6-chloro-5-(5-fluoro-2-30 methoxy-phenoxy)-pyrimidin-4-yl]-4-trifluoromethyl-benzene-sulphonamide and sodium ethylene glycolate there was obtained N- [5 -(S -fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-4-trifluoromethyl-benzenesulphonamide, m.p.
154-155~C (from isopropyl ether).
3s The N- [6-chloro-S -(S -fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-4-trifluoromethyl-benzenesulphonamide (m.p.
185-186~C) was prepared from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine and 4-trifluoromethylbenzene-sulphonamide K.

Example 67 s In analogy to Example 50, but with a reaction temperature of 1 00~C, from 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulphon- amide and sodium ethylene glycolate in ethylene glycol there was obtained lo 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulphon- amide as a solid. Sodium salt: m.p. 195-198~C.

The 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-5 pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide was prepared starting from pyrimidine-2-carboxamidine hydro-chloride via rac-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-tetrahydro-pyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine.
Example 68 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl] -benzenesulphon-2s amide and Na ethylene glycolate in ethylene glycol there wasobtained 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulphonamide as a solid.

The 4-tert-butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2,2'-30 bipyrimidin-4-yl]-benzenesulphonamide was prepared starting from rac-5-(3 -methoxy-phenoxy)-2-(pyrimidin-2-yl)- 1,4,5 ,6-tetrahydro-pyrimidine-4,6-dione via 4,6-dichloro-5-(3-methoxy-phenoxy)-2,2'-bipyrimidinyl.

Example 69 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulphonamide and Na ethylene glycolate in ethylene glycolthere was obtained 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2,2'-bipyrimidi n-4-yl]-benzenesulphonamide, m.p. 161-1 63~C.
s The 4-tert-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulphonamide (m.p. 225-227~C) was prepared starting from diethyl (4-fluoro-2-methoxy-phenoxy)malonate via 5-(4-fluoro-2-methoxy-phenoxy)-2,2'-bipyrimidine-4,6-diol (decomposition point >131 ~C) and 4,6-dichloro-5-(4-fluoro-2-methoxy-phenoxy)-2,2'-bipyrimidine (m.p. 179-1 80~C).

Example 70 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide and Na ethylene glycolate in ethylene glycol there was obtained 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-20 phenoxy)-6-(2-hydroxy-ethoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide, m.p. 141-1 42~C (from CH2CI2-isopropyl ether) .

The 4-tert-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-25 phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide (m.p.
164-1 65~C) was prepared starting from diethyl (4-fluoro-2-methoxy-phenoxy)malonate via rac-5-(4-fluoro-2-methoxy-phenoxy)-2-methyl-1,4,5,6-tetrahydropyrimidine-4,6-dione and 4,6-dichloro-5-(4-fluoro-2-methoxy-phenoxy)-2-methyl-30 pyrimidine (m.p. 129-1 30~C).

Example 71 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-3s (4-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphon-amide and Na ethylene glycolate in ethylene glycol there was obtained 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl~-benzenesulphonamide, m.p. 143-1 44~C (from CH2CI2-isopropyl ether) .

The 4-tert-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-s phenoxy)-pyrimidin-4-yl]-benzenesulphonamide (m.p. 146-1 47~C) was prepared starting from diethyl (4-fluoro-2-methoxy-phenoxy)malonate via rac-5-(4-fluoro-2-methoxy-phenoxy)-1,4,5,6-tetrahydro-pyrimidine-4,6-dione and 4,6-dichloro-5-(4-fluoro-2-methoxy-phenoxy)pyrimidine (m.p. 100-101 ~C).

Example 72 In analogy to Example 50, from N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-4-isopropyl-benzenesulphon-amide and Na ethylene glycolate in ethylene glycol there was obtained N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-4-isopropyl-benzenesulphonamide, m.p.
131-1 32~C (from isopropyl ether).

Example 73 In analogy to Example 50, from N [6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzene-sulphonamide and Na ethylene glycolate in ethylene glycol there 25 was obtained N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidine-4-yl]-4-tert-butyl-benzenesulphonamide, m.p. 126-1 27~C (from isopropyl ether).

The N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-30 pyrimidin-4-yl]-4-isopropyl-benzenesulphonamide, m.p. 138-1 39~C, was prepared starting from diethyl (5-fluoro-2-methoxy-phenoxy)malonate via rac-5-(5-fluoro-2-methoxy-phenoxy)-tetrahydro-pyrimidine-4,6-dione, 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine (m.p. 98-1 00~C) and N-[6-chloro-5-3s (5-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide (m.p. 163-1 64~C).

-Example 74 In analogy to Example 50, from 4-tert-butyl-N-[6-chloro-5-(2-fluoro-6-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphon-5 amide and Na ethylene glycolate in ethylene glycol there was obtained 4-tert-butyl-N-[5-(2-fluoro-6-methoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide, m.p. 158-1 59~C
(from CH2CI2-isopropyl ether).

o The 4-tert-butyl-N-[6-chloro-5-(2-fluoro-6-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide (m.p. 181-1 82~C) was prepared starting from diethyl 2-(2-fluoro-6-methoxy-phenoxy)malonate via rac-5-(2-fluoro-6-methoxy-phenoxy)-1,4,5,6-tetrahydro-pyrimidine-4,6-dione and 4,6-dichloro-5-(2-S fluoro-6-methoxy-phenoxy)-pyrimidine (m.p. 78-79~C).

Example 75 In analogy to Example S0, from 4-tert-butyl-N-[6-chloro-S-20 (3-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulphonamide and Na ethylene glycolate in ethylene glycol there was obtained 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5 -(3 -methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin -4-yl] -benzenesulphonamide, m.p. 159-161 ~C (toluene/n-hexane).
The 4-tert-butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2-(thiophene-2-yl)-pyrimidin-4-yl]-benzenesulphonamide (m.p.
206-207~C) was prepared starting from rac-5-(3-methoxy-phenoxy)-2-(thiophen-2-yl)-3 ,4,5 ,6-tetrahydropyrimidine-4,6-30 dione via 4,6-dichloro-5-(3-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidine (m.p. 120-121 ~C).

Example 76 3s In analogy to Example S0, from 4-tert-butyl-N-[6-chloro-2-(2-methoxy-ethyl)-S -(3-methoxy-phenoxy)-pyrimidin-4-yl] -benzenesulphonamide and Na ethylene glycolate in ethylene glycol there were obtained, after separation by chromatography on silica gel, 4-tert-butyl-N- [6-(2-hydroxy-ethoxy)-2-(2-methoxy-ethyl)-5 -(3 -methoxy-phenoxy)-pyrimidin-4-yl] -benzenesulphonamide and 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-[2-(2-hydroxy-ethoxy)-ethyl] -5 -(3-methoxy-phenoxy)-s pyrimidin-4-yl]-benzenesulphonamide.

The 4-tert-butyl-N-[6-chloro-2-(2-methoxy-ethyl)-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide was prepared starting from methoxypropionamidine hydrochloride via 10 2-(2-methoxy-ethyl)-5-(3-methoxy-phenoxy)-1,4,5,6-tetra-hydro-pyrimidine-4,6-dione and 4,6-dichloro-2-(2-chloro-ethyl)-5 -(3 -methoxy -phenoxy)-pyrimidine.

Example 77 In analogy to Example 50, from p-tert-butyl-N-[6-chloro-5-(o-methoxy -phenoxy)-2-methyl-4-pyrimidinyl] -benzene-sulphonamide and (S)-2,2-dimethyl- 1,3 -dioxolane-4-methanol Na there was obtained (S)-4-tert-butyl-N-[6-(2,2-dimethyl- 1,3-20 dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide, m.p. 124-125~C (from n-hexane).

Example 78 2s A solution of 1.85 g of (S)-4-tert-butyl-N-[6-(2,2-dimethyl-1 ,3 -dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide in EtOH (15 ml) was treated with 3 ml of conc. HCI and heated to 50~C for 2 minutes.
30 After evaporation the residue was extracted with ether and yielded (R)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin -4-yl] -benzenesulphonamide as a foam.

3 5 Example 79 From N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide and (R)-2,2-dimethyl- 1 ,3-dioxolane-4-methanol Na there was obtained (R)-4-tert-butyl-N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2,2-dimethyl-1 ,3 -dioxolan-4-ylmethoxy) -pyrimidin-4-yl] -benzenesulphon -amide (m.p. >86~C). Treatment with dilute hydrochloric acid s yielded (S)-4-tert-butyl-N-5-(fluoro-2-methoxy-phenoxy)-6-(2,3-dihydroxy-propoxy)-pyrimidin-4-yl]-benzenesulphonamide as a foam.

Example 80 From N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide and (S)-2,2-dimethyl- 1 ,3-dioxolane-4-methanol sodium salt there was obtained (S)-4-tert-butyl-N-[5-(5-fluoro-2-methoxy-phenoxy)-6-5 (2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-pyrimidin-4-yl]-benzenesulphonamide (m.p. >86~C). Treatment with dilute HCl yielded (R)-4-tert-butyl-N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2,3 -dihydroxy-propoxy)-pyrimidin-4-yl] -benzenesulphonamide as a foam.
Example 8 1 From 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulphonamide and (S)-25 2,2-dimethyl- 1 ,3-dioxolane-4-methanol sodium salt there was obtained 4-tert-butyl-N-[6-[(S)-1,3-dioxolan-4-ylmethoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl] -benzene-sulphonamide as a foam. Treatment with dilute hydrochloric acid in dioxan yielded (R)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-30 5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulphonamide as a foam.

Example 82 From 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulphonamide and (R)-2,2-dimethyl- 1 ,3-dioxolan-4-methanol sodium salt there was obtained 4-tert-butyl-N-[6-(R)-1,3-dioxolan-4-ylmethoxy]-5-(2-. .
methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl] -benzene-sulphonamide and therefrom with dilute HCl in dioxan there was obtained (S)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl] -s benzenesulphonamide.

Example B3 - From 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-1 o (thiophen-3 -yl)-pyrimidin-4-yl] -benzenesulphonamide and (R)-2,2-dimethyl- 1 ,3-dioxolane-4-methanol sodium salt there was obtained (R)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-5 -(2-methoxy-phenoxy)-2-(thiophen-3 -yl) -pyrimidin-4-yl]-benzenesulphonamide and therefrom with dilute 5 HCl in dioxan there was obtained 4-tert-butyl-N-[6-[(S)-2,3-dihydroxy-propoxy] -5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin -4-yl] -benzenesulphonamide.

Example 84 From 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulphonamide and (S)-2,2-dimethyl- 1 ,3-dioxolane-4-methanol sodium salt there was obtained (S)-4-tert-butyl-N-[(2,2-dimethyl-1,3-dioxolan-4-2s ylmethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulphonamide and therefrom with dilute HCl in dioxan there was obtained 4-tert-butyl-N-[6-[(R)-2,3-dihydroxy-propoxy] -5 -(2-methoxy-phenoxy)-2-(thiophen-3 -yl)-pyrimidin-4-yl] -benzenesulphonamide.
Example 85 From 4-tert-butyl-N-[6-chloro-2-(furan-3-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide and 3s (S)-2,2-dimethyl-1,3-dioxolane-4-methanol sodium salt there was obtained (S )-4-tert-butyl-N- [6 -(2,2-dimethyl- 1 ,3 -dioxolan -4-ylmethoxy)-2-(furan -3-yl)-5 -(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide and therefrom with dilute HCI in dioxan there was obtained (R)-4-tert-butyl-N-[2-(furan-3-yl)-6-(2,3-dihydroxy-propoxy)-5 -(2-methoxy-phenoxy)-pyrimidin -4-yl] -benzenesulphonamide.

s Example 86 From 4-tert-butyl-N-[6-chloro-2-(furan-3-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide and (R)-2,2-dimethyl- 1 ,3-dioxolane-4-methanol sodium salt there was lo obtained (R)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-2-(furan-3 -yl)-5 -(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide and therefrom with dilute HCl in dioxan there was obtained (S)-4-tert-butyl-N-[2-(furan-3-yl)-6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl] -5 benzenesulphonamide.

Example 87 By reaction of p-t-butyl-N-[6-(2-hydroxy-ethoxy)-5-(m-20 methoxy-phenoxy)-4-pyrimidinyl]benzenesulfonamide and 3-methyl-5-isoxazole carboxylic acid in the presence of dimethyl-amino pyridine and dicyclohexylcarbodiimide in methylene chloride there was obtained 3-methylisoxazole-5-carboxylic acid 2-[6-(4-t-butylbenzenesulfonamino)-5-(3-methoxy-phenoxy)-2s pyrimidin-4-yloxy]ethyl ester as a white solid.

Example 88 In analogy to Example 87 employing indole-2-carboxylic 30 acid there was obtained indole-2-carboxylic acid 2-[6-(4-t-butyl-benzenesulfonamino)-5 -(3 -methoxyphenoxy)pyrimidin-4-yloxy] -ethyl ester.

Example 89 3s To a solution of 391.5 mg of 6-[2-(t-butyl-dimethylsilyl-oxy)ethoxy]-5-(2-methoxyphenoxy)pyrimidin-4-yl-amine in 20 ml of acetonitril there were added 200 mg of NaH (60%) and ..
the reaction mixture was stirred for one hour at room tempera-ture. 400 mg of (2-methoxy-5-chlorosulfonyl)phenoxyacetic acid ethyl ester were added. The reaction mixture was stirred for 3.5 hours at room temperature, poured on ice and extracted with s ethyl acetate. The organic phase was dried and evaporated.
Chromatography on silica gel with methylene chloride/methanol (120:1) afforded 175 mg of 4-[6-[2-(t-butyl-dimethylsilyoxy)-ethoxy] -5-(2-methoxyphenoxy)pyrimidin-4-yl-aminosulfonyl] -2-methoxyphenoxy acetic acid ethyl ester as a white foam. That o compound was dissolved in 6 ml of acetonitril and 1 ml of aqueous hydrogen fluoride (40%) were added slowly at 0~C. The reaction mixture was stirred for 30 minutes at 0~C and for 90 minutes at room temperature, poured on ice/2N KHCO3 solution and extracted with methylene chloride. The organic phase was S dried and evaporated and the residue chromatographed on silica gel with methylene chloride/methanol (10: 1). There was obtained 5 - [N- [6-(2 -hydroxyethoxy)-5 -(2-methoxyphenoxy)pyrimidin-4-yl]aminosulfonyl]-2-methoxyphenoxy acetic acid ethyl ester as a white solid.
The starting material was prepared as follows:

Ca. 105 ml of ammonia were passed into a solution of 7 g of 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine in 140 ml of 25 ethanol at -78~C. The reaction mixture was stirred for 15 hours at -78~C and for 50 hours at room temperature and then concen-trated. The residue was distributed between ethyl acetate and water and the organic phase worked up. There were obtained 6.45 g of 4-amino-6-chloro-5-(o-methoxyphenoxy)pyrimidine as 30 white crystals.

2.3 g of the above obtained compound were added to a solution of 250 mg of sodium in 40 ml of ethylene glycol at 50~C.
The solution was heated to 100~C for 12 hours, distributed 35 between half-saturated aqueous NH4CI solution and methylene chloride and the organic phase worked up. There were obtained 2.49 g 2-[6-amino-5-(o-methoxyphenoxy)-4-pyrimidinyl]- 1 -ethanol as white crystals.

To a solution of 2.5 g of the above obtained compound in 100 ml of methylene chloride, 2.74 g of dimethylamino pyridine and 3.39 g of t-butyl dimethylchlorosilane were added and the s mixture was stirred at room temperature for 48 hours. A further 1.35 g of dimethylamino pyridine and 1.65 g of t-butyl dimethyl-chlorosilane were then added and the reaction mixture stirred for another 18 hours at room temperature. The reaction mixture was filtered, the filtrate concentrated and the residue distributed 0 between half-saturated aqueous NH4Cl solution and ethyl acetate.
Work-up of the organic phase yielded 2.78 g of 6-[2-(t-butyl-dimethylsilyloxy]-5-(2-methoxyphenoxy)pyrimidin-4-yl amine as a white solid.

Example A

Tablets containing the following ingredients can be manufactured in a conventional manner:

In~redients Per tablet Compound of formula 1 10.0- 100.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg ExamDle B

Capsules containing the following ingredients can be manufactured in a conventional manner:
2s Ingredients Per capsule Compound of formula 1 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg .

- FY~ le C

Injection solutions can have the following composition:
s Compound of formula 1 3.0 mg Gelatine - 150.0 mg Phenol 4.7 mg Water for injection solutions ad 1.0 ml Example D

500 mg of compound of formula I are suspended in 3.5 ml o of Myglyol 812 and 0.089 of benzyl alcohol. This suspension is filled into a container having a dosage valve. 5.0 9 of Freon 12 *
under pressure are filled into the container through the valve.
The Freon is dissolved in the Myglyol-benzyl alcohol mixture by shaking. This spray container contains about 100 single dosages 15 which can be applied individually.

*
~ Trade mark .~ .

Claims (27)

1. Compounds of the formula wherein R1 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl;
R2 signifies hydrogen, halogen, lower-alkoxy, trifluoromethyl or OCH2COORa; and R3 signifies hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
R4 signifies hydrogen, lower-alkyl, cycloalkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy, lower-alkylsulphinyl, lower-alkylsulphonyl, 2-methoxy-3-hydroxypropoxy,
2-hydroxy-3-phenylpropyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino-arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl or heterocyclyl selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
R5 signifies hydrogen, lower-alkyl, lower-alkanoyl, benzoyl, heterocyclylcarbonyl, heterocyclylmethyl or tetrahydropyran-2-yl, wherein the heterocyclyl is selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
R6 to R9 signify hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkyloxy-carbonyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
Z signifies -O-, -S-, vinylene, -CO-, -OCHR10- or -SCHR10;
R10 signifies hydrogen or lower-alkyl;
X and Y each independently signify O, S or NH; or YR5 also signifies lower-alkylsulphinyl or -OCH2CH(ORC)CH2ORd;
Ra Rb, Rc and Rd each independently signify hydrogen or lower-alkyl;
or Rc and Rd together signify methylene, ethylene or isopropylidene;
and n signifies 1, 2 or 3, wherein cycloalkyl is a residue of 3 to 8 C atoms, and aryl is a phenyl residue,or phenyl substituted by halogen, lower-alkyl, lower-alkoxy, carboxyl or trifluoromethyl; and salts thereof.

2. Compounds of formula I of claim 1, wherein R1 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl;
R2 signifies hydrogen, halogen, lower-alkoxy or trifluoro-methyl; and R3 signifies hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, cycloalkyl, lower-alkoxy or trifluoro-methoxy; or R2 and R3 together signify butadienyl or methylenedioxy;
R4 signifies hydrogen, lower-alkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, amino-lower-alkyl, lower-alkyl-amino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl or heterocyclyl;
R5 signifies hydrogen, lower-alkanoyl, benzoyl or tetrahydro-pyran-2-yl;
R6 to R9 signify hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkyloxy-carbonyloxy; or R7 together with R6 or R8 signify butadienyl or -OCH2O-;
Z signifies -O-, -S-, vinylene, -CO-, -OCHR10- or -SCHR10;
R10 signifies hydrogen or lower-alkyl;
X and Y each independently signify O, S or NH;
Ra and Rb signify hydrogen; and n signifies 1, 2 or 3, wherein cycloalkyl is a residue of 3 to 8 C atoms, and aryl is a phenyl residue, or phenyl substituted by halogen, lower-alkyl, lower-alkoxy, carboxyl or trifluoromethyl; and salts thereof.

3. Compounds according to claim 1 in which Z is -O-.
4. Compounds according to claim 1, in which R6 signifies lower-alkoxy and R7, R8 and R9 signify hydrogen.
5. Compounds according to any one of claims 1-3, in which R6 and R8 signify hydrogen, R7 signifies lower-alkoxy and R9 signifies halogen.
6. Compounds according to any one of claims 14, in which R4 is hydrogen, 2-pyrimidinyl, 2- or 3-furyl, 2- or 3-thienyl, morpholino or p-methoxyphenyl.
7. Compounds according to any one of claims 1, 3 or 4 in which YR5 is hydroxy, or furoyloxy.
8. The compounds according to claim 3, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimi-dinyl]-p-isopropylbenzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-tolyloxy)-4-pyrimidinyl]benzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-chlorophenyloxy)-4-pyrimidinyl]benzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-chlorophenoxy)-4-pyrimi-dinyl]-p-isopropylbenzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-phenoxy-4-pyrimi-dinyl]benzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-ethoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, p-(2,2-dimethylpropyl)-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, p-isopropyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, N-[6-(2-hydroxyethoxy)-6-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-o-toluenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-2,4-xylenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-[(2-methoxy-p-tolyl)-oxy]-4-pyrimidinyl]benzenesulphonamide, N-[5-(2-methoxy-4-methylphenoxy)-6-(2-hydroxyethoxy-4-pyrimidinyl]-p-iso-propylbenzenesulphonamide, N-[5-(2-methoxy-4-methylphenoxy)6-(2-hydroxyethoxy)-4-pyrimidinyl]-o-ethylbenzenesulphonamide, p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphen-oxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, N-16-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(tri-fluoromethyl)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphen-oxy)-2-(trifluoromethyl)-4-pyrimidinyl]benzenesulphonamide, N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-tertbutylbenzenesulphonamide, N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimi-dinyl]-o-methoxybenzenesulphonamide, p-tert-butyl-N-[6-(4-hydroxybutoxy)-5-(o-methoxyphen-oxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(2-naphthyloxy)-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(2-naphthyloxy)-4-pyrimidinyl]-p-tert-butylbenzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]-p-isopropylbenzenesulphonamide, p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphen-oxy)-2-propyl-4-pyrimidinyl]benzenesulphonamide, .alpha.,.alpha.,.alpha.-trifluoro-N-16-(2-hydroxyethoxy)-5-(o-methoxyphen-oxy)-2-methyl-4-pyrimidinyl]-p-toluenesulphonamide, p-chloro-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-(trifluoromethoxy)benzenesulphonamide, o-ethyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-toluenesulphonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-naphthylsulphonamide, p-tert-butyl-N-[6-(3-hydroxypropoxy)-5-(o-methoxyphen-oxy)-2-methyl-4-pyrimidinyl]benzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-[(o-methylthio)-phenoxy]-4-pyrimidinyl]benzenesulphonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]benzenesulphonamide, N-12-amino-6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-p-t-butylbenzenesulphonamide, p-t-butyl-N-16-(2-hydroxyethoxy)-2-methyl-5-[o-(methylthio)phenoxy]-4-pyrimidinyl]benzenesulphonamide and p-t-butyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-[o-(R,S-nethylsulphinyl)phenoxy]-4-pyrimidinyl]benzenesulphonamide.
9. The compounds according to claim 3, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-methyl-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-[(2-(3-furoyloxy)ethoxy]-2-methyl-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-12-(furan-2-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[2-(furan-3-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-(2-hydroxy.ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidin-4-yl]-benzenesulphonamide, 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide, 4-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yll-pyridine 1-oxide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-[2-(2-hydroxy-ethoxy)ethyl]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-12-cyclopropyl-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[2-ethyl-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-isopropyl-5 -(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2,2'-bipyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-methyl-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[5-(2-fluoro-6-methoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-(2-methoxy-ethyl)-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-[2-(2-hydroxy-ethoxy)ethyl]-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamide, (S)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulphonamide, (R)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-methyl-6-(2-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[6-[(S)-1,3-dioxolan-4-ylmethoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzene-sulphonamide, (R)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzene-sulphonamide, 4-tert-butyl-N-[6-(R)-1,3-dioxolan-4-ylmethoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzene-sulphonamide, (S)-4-tert-butyl-N-16-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzene-sulphonamide, (R)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-[(S)-2,3-dihydroxy-propoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzene-sulphonamide, (S)-4-tert-butyl-N-[(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulphonamide, 4-tert-butyl-N-[6-[(R)-2,3-dihydroxy-propoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzene-sulphonamide, (S)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-yl-methoxy)-2-(furan-3-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, (R)-4-tert-butyl-N-[2-(furan-3-yl)-6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamide, (R)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-2-(furan-3-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide, (S)-4-tert-butyl-N-[2-(furan-3-yl)-6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamide, 3-methylisoxazole-5-carboxylic acid 2-[6-(4-t-butyl-benzenesulfonamino)-5-(3-methoxyphenoxy)pyrimidin-4-yloxy]-ethyl ester, indole-2-carboxylic acid 2-[6-(4-t-butylbenzenesulfonamino) -5-(3-methoxyphenoxy)pyrimidin-4-yloxy]ethyl ester, and 5-[N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]aminosulfonyl]-2-methoxyphenoxy acetic acid ethyl ester.
10. (S)-4-tert-Butyl-N-[6-(2,3-dihydroxy-propyloxy)-5-(2-methoxy-phenoxy)-2-(4-methoxyphenyl)-pyrimidin-4-yl]-benzenesulphonamide.
11. (RS)-4-tert-Butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-ethyl-6-(2-methylsulphinyl-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide.
12. (RS)-N-[5-(2-Chloro-5-methoxy-phenoxy)-6-(2-methylsulphinyl-ethoxy)-pyrimidin-4-yl]-1,3-benzodioxol-5-sulphonamide.
13. 4-tert-Butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide.
14. Compounds according to claim 1 or 2, in which Z is vinylene.
15. The compounds according to claim 14, 2-[[5-[(E/Z)-styryl]-6-p-toluenesulphonamido-4-pyrimidinyl]
oxy]ethyl acetate, and N-[6-(2-hydroxyethoxy)-5-([E/Z)-styryl]-4-pyrimidinyl]-p-toluenesulphonamide.
16. Compounds of the formula wherein Hal is halogen;
R1 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl;
R2 signifies hydrogen, halogen, lower-alkoxy, trifluoromethyl or OCH2COORa; and R3 signifies hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
R4 signifies hydrogen, lower-alkyl, cycloalkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, lower-alkoxy-lower alkyl, hydroxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy, lower-alkylsulphinyl, lower-alkylsulphonyl, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenylpropyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino-lower-alkylamino, di-lower-alkylamino-arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl or heterocyclyl selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
R6 to R9 signify hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkoxy-carbonyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
Z signifies -O-, -S-, vinylene, -CO-, -OCHR10- or-SCHR10;
R10 signifies hydrogen or lower-alkyl; and wherein cycloalkyl is a residue of 3 to 8 C atoms, and aryl is a phenyl residue,or phenyl substituted by halogen, lower-alkyl, lower-alkoxy, carboxyl or trifluoromethyl.
17. A process for the manufacture of a compound of any one of claims 1-4, 8-13 or 15, which process comprises:

a) reacting a compound of the formula wherein R1 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl;
R2 signifies hydrogen, halogen, lower-alkoxy, trifluoromethyl or OCH2COORa; and R3 signifies hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
R4 signifies hydrogen, lower-alkyl, cycloalkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, lower-alkoxy-lower alkyl, hydroxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy, lower-alkylsulphinyl, lower-alkylsulphonyl, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenylpropyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino-lower-alkylamino, di-lower-alkylamino-arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl or heterocyclyl selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
R6 to R9 signify hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkoxy-carbonyloxy; or R7 together with R6 or R3 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
Z signifies-O-, -S-, vinylene, -CO-, -OCHR10- or -SCHR10;
R10 signifies hydrogen or lower-alkyl; and Hal is halogen, with a compound of the formula MX(CH2)(CRaRb)nYR5 III
wherein X and Y each independently signify O, S or NH; or YR5 also signifies lower-alkylsulphinyl or -OCH2CH(ORc)CH2ORd;
Ra, Rb, Rc and Rd each independently signify hydrogen or lower-alkyl;
or Rc and Rd together signify methylene, ethylene or isopropylidene; and n signifies 1, 2 or 3, R5 signifies hydrogen, lower-alkyl, lower-alkanoyl, benzoyl, heterocyclylcarbonyl, heterocyclylmethyl or tetrahydropyran-2-yl, wherein the heterocyclyl is selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl, N-oxide 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
and M represents an alkali metal, or b) reacting a compound of the formula wherein R1 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl;
R2 signifies hydrogen, halogen, lower-alkoxy, trifluoromethyl or OCH2COORa; and R3 signifies hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
R4 signifies hydrogen, lower-alkyl, cycloalkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, lower-alkoxy-lower alkyl, hydroxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy, lower-alkylsulphinyl, lower-alkylsulphonyl, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenylpropyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino-lower-alkylamino, di-lower-alkylamino-arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl or heterocyclyl selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
R5 signifies hydrogen, lower-alkyl, lower-alkanoyl, benzoyl, heterocyclylcarbonyl, heterocyclylmethyl or tetrahydropyran-2-yl, wherein the heterocyclyl is selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
X and Y each independently signify O, S or NH; or YR5 also signifies lower-alkylsulphinyl or-OCH2CH(ORc)CH2ORd;
Ra, Rb, Rc and Rd each independently signify hydrogen or lower-alkyl;
or Rc and Rd together signify methylene, ethylene or isopropylidene; and n signifies 1, 2 or 3, with a compound of the formula wherein R6 to R9 signify hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkyloxy-carbonyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; Q is aryl and A- is an anion, or c) reacting a compound of the formula with a compound of the formula wherein R1 signifies hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl;
R2 signifies hydrogen, halogen, lower-alkoxy, trifluoromethyl or OCH2COORa; and R3 signifies hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
R4 signifies hydrogen, lower-alkyl, cycloalkyl, trifluoromethyl, lower-alkoxy, lower-alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, lower-alkoxy-lower alkyl, hydroxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy, lower-alkylsulphinyl, lower-alkylsulphonyl, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenylpropyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino-lower-alkylamino, di-lower-alkylamino-arylamino, aryl, arylthio, aryloxy, aryl-lower-alkyl or heterocyclyl selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl.
R5 signifies hydrogen, lower-alkyl, lower-alkanoyl, benzoyl, heterocyclylcarbonyl, heterocyclylmethyl or tetrahydropyran-2-yl, wherein the heterocyclyl is selected from 2-furyl, 3-furyl, pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridyl N-oxide, 1,2-diazinyl, 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl or heterocyclyl as defined above substituted by lower alkyl, lower alkoxy, halogen, phenyl, or phenyl-lower alkyl;
R6 to R9 signify hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkoxy-carbonyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
Z signifies -O-, -S-, vinylene, -CO-, -OCHR10- or -SCHR10;
R10 signifies hydrogen or lower-alkyl;
X and Y each independently signify O, S or NH; or YR5 also signifies lower-alkylsulphinyl or -OCH2CH(ORc)CH2ORd;

Ra, Rb, Rc and Rd each independently signify hydrogen or lower-alkyl;
or Rc and Rd together signify methylene, ethylene or isopropylidene; and n signifies 1, 2 or 3; and Hal is halogen;
wherein cycloalkyl is a residue of 3 to 8 C atoms, and aryl is a phenyl residue,or phenyl substituted by halogen, lower-alkyl, lower-alkoxy, carboxyl or trifluoromethyl.
18. Pharmaceutical preparations, containing a compound of any one of claims 1-4, 8-13 or 15, and a pharmaceutically acceptable carrier.
19. The use of compounds of any one of claims 1-4, 8-13 or 15, as active ingredients in the manufacture of medicaments, for the treatment of disorders which are associated with endothelin activities.
20. The use of compounds of any one of claims 1-4, 8-13 or 15, as active ingredients for the treatment of disorders which are associated with endothelin activities.
21. Compounds according to claim 2, in which Z is -O-.
22. Compounds according to claim 2 or 3, in which R6 signifies lower-alkoxy and R7, R8 and R9 signify hydrogen.
23. A use in accordance with claim 19, wherein the disorder is a circulatory disorder.
24. A use in accordance with claim 23, wherein the disorder is hypertension, ischemia, vasospasms or angina pectoris.
25. A use in accordance with claim 20, wherein the disorder is a circulatory disorder.
26. A use in accordance with Claim 25 wherein the disorder is hypertension, ischemia, vasospasms or angina pectoris.
27. The process of claim 17 wherein the compound is converted into a salt.
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