Claims for Patent: 5,292,740

Summary for Patent: 5,292,740

Title:	Sulfonamides
Abstract:	The novel sulfonamides of formula I, I in which the symbols R1-R9, Ra, Rb, X, Y and n have the significance given in the description and salts thereof can be used for the treatment of circulatory disorders, especially hypertension, ischemia, vasopasms and angina pectoris.
Inventor(s):	Kaspar Burri, Martine Clozel, Walter Fischli, Georges Hirth, Bernd-Michael Loffler, Werner Neidhart, Henri Ramuz
Assignee:	F Hoffmann La Roche AG , Hoffmann La Roche Inc
Application Number:	US07/896,015
Patent Claims:	1. A compound of the formula ##STR12## wherein R1 is hydrogen, lower-alkyl, lower alkoxy, lower-alkylthio, halogen or trifluoromethyl;R2 is hydrogen, halogen, lower-alkoxy, trifluoromethyl or --OCH2 COORa ; and R3 is hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, C3 -C8 cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; R4 is hydrogen, lower-alkyl, C3 -C8 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, unsubstituted phenyl amino, phenylamino substituted with halogen, lower-alkyl, lower alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl, phenyl substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenylthio, phenylthio substituted with halogen, lower-alkyl, lower alkoxy carboxyl or trifluoromethyl, unsubstituted phenoxy, phenoxy substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl-lower alkyl, phenyl-lower-alkyl substituted with halogen, lower-alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted 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 is hydrogen, lower-alkyl, lower-alkanoyl, benzoyl, heterocyclylcarbonyl wherein the heterocyclyl is selected from unsubstituted 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, phenyl-lower alkyl, heterocyclyl methyl 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, or tetrahydro-pyran-2-yl; R6 to R9 are hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkyloxycarbonyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; Z is --O--, --S--, vinylene, --CO--, OCHR10 -- or --SCHR10 ; R10 is hydrogen or lower alkyl; X and Y each independently are O, S or NH; or YR5 is lower-alkylsulphinyl; Ra, Rb, Rc and Rd each independently are hydrogen or lower-alkyl; or Rc and Rd together are methylene, ethylene or isopropylidene; and n is 1, 2 or 3,or a stereoisomer or salt thereof. 2. The compound of claim 1, whereinR1 is hydrogen lower-alkyl, lower alkoxy, lower-alkylthio, halogen or trifluoromethyl; R2 is hydrogen, halogen, lower-alkoxy or trifluoromethyl; and R3 is hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, C3 -C8 cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, R4 is hydrogen, lower-alkyl, trifluoromethyl, lower-alkoxy, lower alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, amino-lower alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, unsubstituted phenyl amino, phenylamino substituted with halogen, lower-alkyl, lower alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl, phenyl substituted with halogen, lower alkyl, lower-alkoxycarboxyl or trifluoromethyl, unsubstituted phenylthio, phenylthio substituted with halogen, lower-alkyl, lower alkoxy carboxyl or trifluoromethyl, unsubstituted phenoxy, phenoxy substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl-lower alkyl, phenyl-lower-alkyl substituted with halogen, lower-alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted 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 is hydrogen, lower-alkanoyl, benzoyl or tetrahydropyran-2-yl; R6 to R9 are 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 or --OCH2 O--; Z is --O--, --S--, vinylene, --CO--, OCHR10 -- or --SCHR10 ; R10 is hydrogen or lower-alkyl; X and Y each independently are O, S or NH; Ra and Rb are hydrogen; and n is 1, 2 or 3or a stereoisomer or salt thereof. 3. A compound according to claim 1, wherein Z is --O--. 4. A compound according to claim 2, wherein R6 is lower-alkoxy and R7, R8 and R9 are hydrogen. 5. A compound according to claim 2, wherein R6 and R8 are hydrogen, R7 is lower-alkoxy and R9 is halogen. 6. A compound according to claim 1, wherein R4 is hydrogen, 2-pyrimidinyl, 2- or 3-furyl, 2- or 3-thienyl, morpholino or p-methoxyphenyl. 7. A compound according to claim 1, wherein YR5 is hydroxy, lower-alkoxysulphinyl or furoyloxy. 8. A compound according to claim 3, selected from the group consisting ofp-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-tolyloxy)-4-pyrimidinyl]benzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-chlorophenyloxy)-4-pyrimidinyl]benzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-chlorophenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-phenoxy-4-pyrimidinyl]benzenesulfonamide p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-ethoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, p-(2,2-dimethylpropyl)-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, p-isopropyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, N-[6-(2-hydroxyethoxy)-6-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-o-toluenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl]-2,4-xylenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-[(2-methoxy-p-tolyl)oxy]-4-pyrimidinyl]benzenesulfonamide, N-[5-(2-methoxy-4-methylphenoxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-iso-propylbenzenesulfonamide, N-[5-(2-methoxy-4-methylphenoxy)6-(2-hydroxyethoxy)-4-pyrimidinyl]-o-ethylbenzenesulfonamide, p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(trifluoromethyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(trifluoromethyl)-4-pyrimidinyl]benzenesulfonamide, N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-tertbutylbenzenesulfonamide, N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-o-methoxybenzenesulfonamide, p-tert-butyl-N-[6-(4-hydroxybutoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2-naphthyloxy)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2-naphthyloxy)-4-pyrimidinyl]-p-tert-butylbenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]benzenesulfonamide, α,α,α-trifluoro-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-toluenesulfonamide, p-chloro-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-(trifluoromethoxy)benzenesulfonamide, o-ethyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-p-toluenesulfonamide, p-tert-butyl-N-[6-(3-hydroxypropoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-[(o-methylthio)phenoxy]-4-pyrimidinyl]benzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl]benzenesulfonamide, N-[2-amino-6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-p-t-butylbenzenesulfonamide, p-t-butyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-[o-(methylthio)phenoxy]-4-pyrimidinyl]benzenesulfonamide and p-t-butyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-[o-(R,S-methylsulphinyl)phenoxy]-4-pyrimidinyl]benzenesulfonamide. 9. A compound according to claim 3, selected from the group consisting of:4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-methyl-pyrimidin-4-yl]-benzene-sulfonamide, 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-[2-(3-furoyloxy)ethoxy]-2-methyl-pyrimidin-4-yl]-benzene-sulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzene-sulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzene-sulfonamide, 4-tert-butyl-N-[2-(furan-2-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[2-(furan-3-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidin-4-yl]-benzenesulfonamide, 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-yl]-pyridine 1-oxide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-[2-(2-hydroxy-ethoxy)ethyl]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[2-cyclopropyl-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[2-ethyl-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-isopropyl-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-chloro-N-[3-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulfonamide, N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-4-trifluoromethyl-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-methyl-pyrimidin-4-yl]-benzene-sulfonamide, 4-tert-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulfonamide, N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-4-isopropyl-benzenesulfonamide, N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide, 4-tert-butyl-N-[5-(2-fluoro-6-methoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-(2-methoxy-ethyl)-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-2-[2-(2-methoxy-ethoxy)ethyl]-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, 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. The compound, N-[6-(2-hydroxyethoxy)-5-(O-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-naphthylsulfonamide. 11. (S)-4-tert-Butyl-N-[6-(2,3-dihydroxy-propyloxy)-5-(2-methoxy-phenoxy)-2-(4-methoxyphenyl)-pyrimidin-4-yl]-benzenesulfonamide. 12. (RS)-4-tert-Butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-ethyl-6-(2-methylsulphinyl-ethoxy)-pyrimidin-4-yl]-benzenesulfonamide. 13. (RS)-N-[5-(2-Chloro-5-methoxy-phenoxy)-6-(2-methylsulphinyl-ethoxy)-pyrimidin-4-yl]-1,3-benzodioxol-5-sulfonamide. 14. 4-tert-Butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulfonamide. 15. A compound according to claim 2, wherein Z is or vinylene. 16. A compound according to claim 15, selected from the group consisting of2-[[5-[(E/Z)-styryl]-6-p-toluenesulphonamido-4-pyrimidinyl]oxy]ethyl acetate and N-[6-(2-hydroxyethoxy)-5-([E/Z)-styryl]-4-pyrimidinyl]-p-toluenesulfonamide 17. A compound of the formula ##STR13## wherein R1 is hydrogen, lower-alkyl, lower alkoxy, lower-alkylthio, halogen or trifluoromethyl;R2 is hydrogen, halogen, lower-alkoxy, trifluoromethyl or --OCH2 COORa ; and R3 is hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, C3 -C8 cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; R4 is hydrogen, lower-alkyl, C3 -C8 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, unsubstituted phenyl amino, phenylamino substituted with halogen, lower-alkyl, lower alkoxycarboxyl or trifluoromethyl, unsubstituted phenyl, phenyl substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenylthio, phenylthio substituted with halogen, lower-alkyl, lower alkoxy carboxyl or trifluoromethyl, unsubstituted phenoxy, phenoxy substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl-lower alkyl, phenyl-lower-alkyl substituted with halogen, lower-alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted 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 is hydrogen, lower-alkyl, lower alkanoyl, benzoyl, heterocyclylcarbonyl wherein the heterocyclyl is selected from unsubstituted 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, phenyl-lower alkyl, heterocyclyl methyl 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, or tetrahydropyran-2-yl; Z is --O--, --S--, vinylene, --CO--, OCHR10 -- or --SCHR10 ; R10 is hydrogen or lower-alkyl; Ra and Rb each independently are hydrogen or lower-alkyl; and n is 1, 2 or 3. 18. A pharmaceutical composition comprising a compound of the formula ##STR14## wherein R1 is hydrogen, lower-alkyl, lower alkoxy, lower-alkylthio, halogen or trifluoromethyl;R2 is hydrogen, halogen, lower-alkoxy, trifluoromethyl or --OCH2 COORa ; and R3 is hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, C3 -C8 cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together are butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; R4 is hydrogen, lower-alkyl, C3 -C8 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-hydroxyproxy, 2-hydroxy-3-phenylpropyl, amino-lower alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, unsubstituted phenyl amino, phenylamino substituted with halogen, lower-alkyl, lower alkoxycarboxyl or trifluoromethyl, unsubstituted phenyl, phenyl substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenylthio, phenylthio substituted with halogen, lower-alkyl, lower alkoxy carboxyl or trifluoromethyl, unsubstituted phenoxy, phenoxy substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl-lower alkyl, phenyl-lower-alkyl substituted with halogen, lower-alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted 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 is hydrogen, lower-alkyl, lower alkanoyl, benzoyl, heterocyclylcarbonyl wherein the heterocyclyl is selected from unsubstituted 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, phenyl-lower alkyl, heterocyclyl methyl 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, or tetrahydropyran-2-yl; R6 to R9 are hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkyloxy-carboyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; is --O--, --S--, vinylene, --CO--, OCHR10 -- or --SCHR10 ; R10 is hydrogen or lower alkyl; X and Y each independently are O, S or NH; or YR5 is lower-alkylsulphinyl; Ra, Rb, Rc and Rd each independently are hydrogen or lower-alkyl; or Rc and Rd together signify methylene, ethylene or isopropylidene; and n is 1, 2 or 3or a stereoisomer or salt thereof and an inert carrier. 19. The pharmaceutical composition of claim 18, whereinR1 is hydrogen, lower-alkyl, lower alkoxy, lower-alkylthio, halogen or trifluoromethyl; R2 is hydrogen, halogen, lower-alkoxy, trifluoromethyl; R3 is hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, C3 -C8 cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together are butadienyl, methylenedioxy; R4 is hydrogen, lower-alkyl, trifluoromethyl, lower-alkoxy, lower alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, amino-lower alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, unsubstituted phenyl amino, phenylamino substituted with halogen, lower-alkyl, lower alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl, phenyl substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenylthio, phenylthio substituted with halogen, lower-alkyl, lower alkoxy carboxyl or trifluoromethyl, unsubstituted phenoxy, phenoxy substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl-lower alkyl, phenyl-lower-alkyl substituted with halogen, lower-alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted 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 is hydrogen, lower-alkanoyl, benzoyl or tetrahydropyran-2-yl; R6 to R9 are hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkoxy-carboyloxy; or together with R6 or R8 signify butadienyl or --OCH2 O--; Z is --O--, --S--, vinylene, --CO--, OCHR10 -- or --SCHR10 ; R10 is hydrogen or lower-alkyl; X and Y each independently are O, S or NH; Ra and Rb are hydrogen; and n is 1, 2 or 3or a stereoisomer or salt thereof. 20. A method of treating disorders associated with endothelin activities comprising administering to a host in need of such treatment an effective amount of a compound of the formula ##STR15## wherein R1 is hydrogen, lower-alkyl, lower alkoxy, lower-alkylthio, halogen or trifluoromethyl;R2 is hydrogen, halogen, lower-alkoxy, trifluoromethyl or --OCH2 COORa ; R3 is hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, C3 -C8 cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; R4 is hydrogen, lower-alkyl, C3 -C8 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, unsubstituted phenyl amino, phenylamino substituted with halogen, lower-alkyl, lower alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl, phenyl substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenylthio, phenylthio substituted with halogen, lower-alkyl, lower alkoxy carboxyl or trifluoromethyl, unsubstituted phenoxy, phenoxy substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl-lower alkyl, phenyl-lower-alkyl substituted with halogen, lower-alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted 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 is hydrogen, lower-alkyl, lower-alkanoyl, benzoyl, heterocyclylcarbonyl wherein the heterocyclyl is selected from unsubstituted 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, phenyl-lower alkyl, heterocyclyl methyl 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, or tetrahydro-pyran-2-yl; R6 to R9 are hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkyloxycarbonyloxy; or R7 together with R6 or R8 signify butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; is --O--, --S--, vinylene, --CO--, OCHR10 -- or --SCHR10 ; R10 is hydrogen or lower-alkyl; X and Y each independently are O, S or NH; or YR5 is lower-alkylsulphinyl; Ra, Rb, Rc and Rd each independently are hydrogen or lower-alkyl; or Rc and Rd together signify methylene, ethylene or isopropylidene; and n is 1, 2 or 3or a stereoisomer or salt thereof. 21. The method of claim 20, whereinR1 is hydrogen, lower-alkyl, lower alkoxy, lower-alkylthio, halogen or trifluoromethyl; R2 is hydrogen, halogen, lower-alkoxy, trifluoromethyl; R3 is hydrogen, halogen, lower-alkyl, lower-alkylthio, trifluoromethyl, C3 -C8 cycloalkyl, lower-alkoxy or trifluoromethoxy; or R2 and R3 together are butadienyl or methylenedioxy; R4 is hydrogen, lower-alkyl, trifluoromethyl, lower-alkoxy, lower alkylthio, lower-alkylthio-lower-alkyl, hydroxy-lower-alkyl, amino-lower alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, unsubstituted phenyl amino, phenylamino substituted with halogen, lower-alkyl, lower alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl, phenyl substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenylthio, phenylthio substituted with halogen, lower-alkyl, lower alkoxy carboxyl or trifluoromethyl, unsubstituted phenoxy, phenoxy substituted with halogen, lower alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted phenyl-lower alkyl, phenyl-lower-alkyl substituted with halogen, lower-alkyl, lower-alkoxy-carboxyl or trifluoromethyl, unsubstituted 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 is hydrogen, lower-alkanoyl, benzoyl or tetrahydropyran-2-yl; R6 to R9 are hydrogen, halogen, trifluoromethyl, lower-alkyl, lower-alkoxy, lower-alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulphinyl, methylsulphonyl, methylsulphonyloxy or lower-alkoxycarbonyloxy; or R7 together with R6 or R8 signify butadienyl or --OCH2 O--; Z is --O--, --S--, vinylene, --CO--, OCHR10 -- or --SCHR10 ; R10 is hydrogen or lower-alkyl; X and Y each independently are O, S or NH; Ra and Rb are hydrogen; and n is 1, 2 or 3or a stereoisomer or salt thereof. 22. The pharmaceutical composition of claim 18, wherein Z is --O--. 23. The pharmaceutical composition of claim 19, R6 is lower-alkoxy and R7, R8 and R9 are hydrogen. 24. The pharmaceutical composition of claim 19, wherein R6 and R8 are hydrogen, R7 is lower-alkoxy and R9 is halogen. 25. The pharmaceutical composition of claim 18, wherein R4 is hydrogen, 2-pyrimidinyl, 2- or 3-furyl, 2- or 3-thienyl, morpholino or p-methoxyphenyl. 26. The method of claim 20, wherein the disorder is a circulatory disorder. 27. The method of claim 26, wherein the circulatory disorder is hypertension, ischemia, vasopasms or angina pectoris. 28. The method of claim 20, wherein Z is --O--. 29. The method of claim 21, wherein R6 is lower-alkoxy and R7, R8 and R9 are hydrogen. 30. The method of claim 21, wherein R6 and R8 are hydrogen, R7 is lower-alkoxy and R9 is halogen. 31. The method of claim 20, wherein R4 is hydrogen, 2-pyrimidinyl, 2- or 3-furyl, 2- or 3-thienyl, morpholino or p-methoxyphenyl. 32. A compound of the formula ##STR16## wherein R1 is hydrogen;R2 is hydrogen; R3 is lower alkyl; R4 is hydrogen, lower-alkyl, 2-thienyl, 3-thienyl or 3-furyl; R6 is lower-alkoxy; R7 to R9 are hydrogen; R11 is halogen Z is --O-- W is 1,3-dioxolan-4-ylmethoxy, 2,2-dimethyl-1,3-dioxolan-4-ylmethoxy or 2,3-dihydroxy-propoxyor a stereiosomer or salt thereof. 33. A compound according to claim 32 selected from the group consisting of:(S)-4-tert-butyl-N-[6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulfonamide, (R)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy-5-(2-methoxy-phenoxy)-2-methyl-6-(2-pyrimidin-4-yl]-benzenesulfonamide, (R)-4-tert-butyl-N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-pyrimidin-4-yl]-benzenesulfonamide, (S)-4-tert-butyl-N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-pyrimidin-4-yl]-benzenesulfonamide, (R)-4-tert-butyl-N-(5-fluoro-2-methoxy-phenoxy)-6-(2,3-dihydroxy-propoxy-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-[(S)-1,3-dioxolan-4-ylmethoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulfonamide, (R)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-(R)-1,3-dioxolan-4-lymethoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulfonamide, (S)-4-tert-butyl-N-[6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulfonamide, (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]-benzenesulfonamide, 4-tert-butyl-N-[6-[(S)-2,3-dihydroxy-propoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulfonamide, (S)-4-tert-butyl-N-[(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulfonamide, 4-tert-butyl-N-[6-[(R)-2,3-dihydroxy-propoxy]-5-(2-methoxy-phenoxy)-2-(thiophen-3-yl)-pyrimidin-4-yl]-benzenesulfonamide, (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]-benzenesulfonamide, (R)-4-tert-butyl-N-[2-(furan-3-yl)-6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide, (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]-benzenesulfonamide; and (S)-4-tert-butyl-N-[2-(furan-3-yl)-6-(2,3-dihydroxy-propoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide.