NO327755B1 - Svovelsubstituerte sulfonylaminokarboksylsyre N-arylamider, deres fremstilling og anvendelse samt farmasoytiske preparater inneholdende forbindelsene - Google Patents
Svovelsubstituerte sulfonylaminokarboksylsyre N-arylamider, deres fremstilling og anvendelse samt farmasoytiske preparater inneholdende forbindelsene Download PDFInfo
- Publication number
- NO327755B1 NO327755B1 NO20010013A NO20010013A NO327755B1 NO 327755 B1 NO327755 B1 NO 327755B1 NO 20010013 A NO20010013 A NO 20010013A NO 20010013 A NO20010013 A NO 20010013A NO 327755 B1 NO327755 B1 NO 327755B1
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- chloro
- phenyl
- formula
- benzamide
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 115
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 10
- -1 Sulfur-substituted sulfonylaminocarboxylic acid Chemical class 0.000 title description 45
- 125000001424 substituent group Chemical group 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 238000002560 therapeutic procedure Methods 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 238000011321 prophylaxis Methods 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 5
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
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- 206010020772 Hypertension Diseases 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- WZHRJGWXUCLILI-UHFFFAOYSA-N sulfonylcarbamic acid Chemical compound OC(=O)N=S(=O)=O WZHRJGWXUCLILI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 3
- YFJKHTZXXMBJEW-UHFFFAOYSA-N 2-[(4-chlorophenyl)sulfonylamino]-4,5-dimethoxy-n-(4-thiomorpholin-4-ylsulfonylphenyl)benzamide Chemical group C=1C=C(S(=O)(=O)N2CCSCC2)C=CC=1NC(=O)C=1C=C(OC)C(OC)=CC=1NS(=O)(=O)C1=CC=C(Cl)C=C1 YFJKHTZXXMBJEW-UHFFFAOYSA-N 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
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- 125000000524 functional group Chemical group 0.000 claims description 3
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- 239000002243 precursor Substances 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 2
- NDUZZUGMFXHNMT-UHFFFAOYSA-N 5-chloro-2-[(5-chlorothiophen-2-yl)sulfonylamino]-n-(4-morpholin-4-ylsulfonylphenyl)benzamide;sodium Chemical group [Na].S1C(Cl)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1C(=O)NC1=CC=C(S(=O)(=O)N2CCOCC2)C=C1 NDUZZUGMFXHNMT-UHFFFAOYSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 2
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- KRLMQTYZKFWKMJ-GASCZTMLSA-N 5-chloro-n-[4-[(2r,6s)-2,6-dimethylmorpholin-4-yl]sulfonylphenyl]-2-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonylamino]benzamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1S(=O)(=O)C(C=C1)=CC=C1NC(=O)C1=CC(Cl)=CC=C1NS(=O)(=O)C1=C(C)ON=C1C KRLMQTYZKFWKMJ-GASCZTMLSA-N 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- FAQOZARUOBFXBH-UHFFFAOYSA-N nitroformamide Chemical compound NC(=O)[N+]([O-])=O FAQOZARUOBFXBH-UHFFFAOYSA-N 0.000 claims 1
- 159000000000 sodium salts Chemical group 0.000 claims 1
- 238000002844 melting Methods 0.000 description 147
- 230000008018 melting Effects 0.000 description 147
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 20
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 20
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 16
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical group O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
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- 230000004913 activation Effects 0.000 description 11
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Classifications
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Description
Foreliggende oppfinnelse angår forbindelser med den generelle formel I
der A,A,R,R,R,X og n er som angitt nedenfor, og som er verdifulle, farmasøytisk aktive forbindelser for terapi og profylakse av sykdommer, for eksempel kardiovaskulære sykdommer som hypertensjon, angina pectoris, kardial insuffisiens, tromboser eller aterosklerose. Forbindelsene med formel I er i stand til å modulere kroppens produksjon av cyklisk guanosinmonofosfat (cGMP) og er generelt egnet for terapi og profylakse av sykdommer som forbindes med en forstyrrelse av cGMP-balansen. Foreliggende oppfinnelse angår videre fremgangsmåter for fremstilling av forbindelsene med formel I, forbindelsene for bruk som farmasøytikum og anvendelse av disse for fremstilling av farmasøytika for terapi og profylakse av de ovenfor nevnte sykdommer, samt farmasøytiske preparater som omfatter forbindelsene med formel I.
cGMP er en viktig intracellulære meddeler som utløser en stor mengde forskjellige effekter via moduleringen av cGMP-avhengige proteinkinaser, fosfordiesteraser og ionekanaler. Eksempler er avslapningen av glatte muskler, inhiberingen av trombocytt-aktivering og inhiberingen av prolifereringen av glatte muskelceller og av leukocytt-adhesjon. cGMP produseres av spesielle og oppløselige guanylatcyklaser som en respons på et antall ekstracellulære og intracellulære stimuli. Når det gjelder de spesielle guanylatcyklaser, effektueres stimuleringen i det vesentlige av peptidiske meddelere som det atriale natriuretiske peptid eller det cerebrale natriuretiske peptid. De oppløselig guanylatcyklaser (sGC) som er cytosoliske heterodimere hemeproteiner blir i motset-ning til dette i det vesentlig regulert av en familie av lav-molekylær vektfaktorer som dannes enzymatisk. Den viktigste stimulant er nitrogenmonoksyd (NO) eller nær beslektede specier. Funksjonen av andre faktorer som karbonmonoksyd eller hydroksyl-
restene er fremdeles i stor grad uklar. Bindingen av NO til heme med dannelse av penta-koordinat heme-nitrosylkompleks diskuteres som aktiveringsmekanisme for aktiveringen med NO. Den assosierte frigivning av histidin som er bundet i basal til jernet konverterer enzymet til den aktive konformasjon.
Aktive, oppløselige guanylatcyklaser består av en a- og en p-subenhet hver. Flere subenheter subtyper er beskrevet som skiller seg fra hverandre når det gjelder sekvenser, vev-spesifikk fordeling og ekspresjon i forskjellige utviklingstrinn. Subtypene ai og pi uttrykkes hovedsakelig i hjernen og lungen, mens P2 særlig finnes i lever og nyrer. Sub-typen 0:2 ble påvist å være til stede i human føtal hjerne. Subenhetene som kalles 0:3 og P3 ble isolert fra human hjerne og homolog til ai og Pi. Senere arbeider antyder en a^-subenhet som inneholder et innskudd i det katalytiske området. Alle subenheter viser store homologier i området for det katalytiske domenet. Enzymene inneholder antagelig et heme pr. heterodimer, som er bundet via Pi-Cys-78 og/eller Pi-His-105 og som er en del av det regulatoriske senter.
Under patologiske betingelser kan dannelsen av guanylatcyklase-aktiverende faktorer reduseres, eller deres nedbrytning kan fremmes på grunn av den økede opptredenen av frie radikaler. Den resulterende, reduserte aktivering av sGC fører via en svekning av den respektive cGMP-medierte cellulære respons, for eksempel til en økning av blodtrykket, til plateaktivering eller til øket celleproliferering og celleadhesjon. Som en konsekvens resulterer dette i dannelse av endotelial dysfunksjon, aterosklerose, hypertensjon, stabil eller ustabil angina pectoris, tromboser, myokardial infarkt, slag eller erektil dysfunksjon. Farmakologisk stimulering av sGC gir en mulighet for å normali-sere cGMP-produksjonen og gjør det derfor mulig med behandling og/eller prevensjon av slike mangler.
For den farmakologiske stimulering av sGC har man hittil så å si utelukkende benyttet seg av forbindelser hvis aktivitet er basert på en intermediat NO-frigivning, for eksempel organiske nitrater. Mangelen ved denne behandling er utviklingen av toleranse og en reduksjon av aktiviteten og de høyere doser som kreves på grunn av dette.
Forskjellige sGC-stimulatorer som ikke virker via NO-frigivning er beskrevet av Vesely i en serie publikasjoner. Imidlertid har forbindelsene, de fleste av hvilke er hormoner, plantehormoner, vitaminer eller naturlige forbindelser som for eksempel firfislegift, har predominant kun svake virkninger på cGMP-dannelsen i cellelysater (D.L. Vesely, "Eur. J. Clin. Invest.", 15 (1985) 258; D.L. Vesely, "Biochem. Biophys. Res. Comm.", 88 (1979) 1244). En stimulering av heme-fri guanylatcyklase med protoporfyrin IX ble påvist av Ignarro et al. i "Adv. Pharmacol.", 26 (1994) 35. Pettibone et al. beskriver i "Eur. J. Pharmacol.", 116 (1985) 307 en antihypertensiv virkning av difenyliodonium-heksafluorfosfat og tilskriver dette en stimulering av sGC. I henhold til Yu et al. i "Brit. J. Pharmacol.", 114 (1995) 1587) aktiverer isoliguiirtigenin, som har en avslappende virkning på isolerte rotteaorta, også sGC. Ko et al. ("Blood", 84 (1994) 4226), Yu et al.
("Biochem. J.", 306 (1995) 787) og Wu et al. ("Brit. J. Pharmacol.", 116 (1995) 1973) viser en sGC-stimulerende aktivitet av l-benzyl-3-(5-hydroksymetyl-2-furyl)indazol og påviste en antiproliferativ og trombocytt-inhiberende virkning. Pyrazoler og fuserte pyrazoler som viser en sGC-stimulerende aktivitet er beskrevet i EP-A-908 456 og DE-A-19744027.
En serie 2-sulfonylaminobenzosyre-N-arylamider hvis N-arylgruppe bærer en tio-substituent har vært nevnt i litteraturen. Disse forbindelser der N-arylgruppen generelt bærer som ytterligere substituenter, grupper som er lett oksyderbare, for eksempel to hydroksygrupper i para-posisjon i forhold til hverandre og som i dette tilfellet kan anses som hydrokinonderivater, er auxilliære for fremstilling av fotografiske materialer (se for eksempel "Chemical Abstracts", 119,105757; 120,41858; 123, 70224 eller 126, 257007). Hvis isolerte, strukturelle elementer betraktes, tilsvarer N-arylgruppen i disse kjente forbindelser gruppen R<1->S(0)n-A<1> i formel I i det tilfellet A<1> angir en 1,4-fenylenrest som i posisjonene 2 og 5 bærer hydroksygrupper (eller oksy-substituenter) og tallet n er 0. Britisk patent publikasjon 876526 ("Chemical Abstracts", 56,15432e) beskriver 3,5-diklor-2-metylsulfonylaminobenzosyre-N-(5-klor-2-(4-klorfenyl-merkapto)-fenyl)-amid som kan benyttes for beskyttelse av ull mot møll. Forbindelser som dekkes av GB-A-876526 tilsvarer forbindelser med formel I hvis samtidig ringen A<1> som omfatter karbonatomene som bærer gruppene C(=X)-NH- og NH-SO2R<2>, sammen med restene R<3>, er en benzenring som bærer 2 til 4 halogenatomer fra seriene klor og brom, R<2> er Ci-4-alkyl, X er oksygen og gruppen R<1->S(0)n-A<1-> er en fenyl-merkaptofenylrest (= fenyltiofenyl-) som er substituert med halogen og/eller trifluormetyl og som også kan være substituert med metyl eller Ci-4-alkoksy, og det totale andre halogenatomer og trifluormetylgrupper er større enn 2. Farmakologiske aktiviteter for disse kjente 2-sulfonylaminobenzosyre-N-arylamider er ikke beskrevet.
Overraskende er det nå funnet at forbindelsene ifølge foreliggende oppfinnelse utøver en sterk aktivering av guanylatcyklase og derfor er egnet for terapi og profylakse av mangler som er forbundet med et lavt cGMP-nivå.
I henhold til dette angår foreliggende oppfinnelse forbindelser med formel I
der
A<1> er fenylen som kan være usubstituert eller substituert med en eller flere identiske eller forskjellige substituenter fra serien halogen, CM-alkyl, CF3, -O-Ci-4-alkyl og -CN;
ringen A som omfatter de to karbonatomene som bærer gruppene R -SO2-NH- og C(=X)-NH- er en benzenring, en pyridinring, en tiofenring eller en pyrazolring;
R<1> er Ci-7-alkyl eller er fenyl som kan være usubstituert eller substituert med en eller flere, like eller forskjellige substituenter fra serien halogen, Ci-4-alkyl, fenyl, CF3, NO2, -O-CM-alkyl, Ci.2-alkylendioksy, NH2, -NH-CO-CM-alkyl, -CN, -CO-NH2, -CO-OH og -CO-O-CM-alkyl; eller hvis tallet n i gruppen R^SCO),,- er 2, kan R<1> også være NR<5>R<6>;
R eraryl;
R<3> angir en eller flere, like eller forskjellige rester fra serien hydrogen, halogen, CF3, - O-CM-alkyl, -CN, og CM-alkyl;
R<5> og R<6> er uavhengig av hverandre hydrogen eller Ci-9-alkyl som kan være usubstituert eller substituert med aryl; eller C2-9-alkenyl, eller C3.9-cykloalkyl, eller Ci-4-alkyl-0-Ci.3-alkyl; eller
R<5> og R<6> danner sammen med nitrogenatomet hvor til de er bundet en 5- til 7-leddet, mettet eller partielt umettet heterocyklyl som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde ett ytterligere ringheteroatomer fra serien N, O og S og som kan være substituert med en eller flere, like eller forskjellige substituenter fra serien Cu-alkyl, hydroksy-Ci-3-alkyl, aryl, karbamoyl, hydroksy og okso, og til hvilken en benzenring kan være kondensert;
aryl er fenyl eller heteroaryl som kan være substituert med en eller flere, like eller forskjellige substituenter fra serien halogen, Ci-4-alkyl, fenyl, CF3, NO2, -O-CM-alkyl, Ci-2-alkylendioksy, NH2, -NH-CO-CM-alkyl, -CN, -CO-NH2, -CO-OH, og -CO-0-CM-alkyl;
heteroaryl er en rest av en monocyklisk, 5- eller 6-leddet aromatisk heterocykel som inneholder ett eller to like eller forskjellige heteroatomer fra serien N, O og S;
n er 0 eller 2;
XerO;
i alle sine stereoisomere former og blandinger derav i alle forhold, og deres fysiologisk akseptable salter; hvor kun opptil to nitrogrupper kan være tilstede i en forbindelse av formel (I).
Hvis grupper eller substituenter kan opptre flere ganger i forbindelsene med formel I som for eksempel R<3>, R<5>, aryl, alkyl, kan de alle uavhengig av hverandre ha de betydninger som er antydet og kan i hvert tilfelle være like eller forskjellige.
Alkylrester kan være rette eller forgrenede. Dette gjelder også der de er deler av andre gruppe, for eksempel alkoksygrupper, alkoksykarbonylgrupper eller aminogrupper, eller når de er substituert. Eksempler på alkylgrupper er metyl, etyl, propyl, butyl, pentyl, heksyl, heptyl, oktyl, nonyl, n-isomerene av disse rester, isopropyl, isobutyl, isopentyl, sek-butyl, tert-butyl, neopentyl, 3,3-dimetylbutyl.
Eksempler på alkenylgrupper det vil si umettet alkylgruppe som inneholder minst to karbonatomer og som inneholder en eller flere dobbeltbindinger er vinylresten, 1-propenylresten, 2-propenylresten (allylrest), 2-butenylresten, 2-metyl-2-propenylresten eller 3-metyl-2-butenylresten.
Eksempler på cykloalkylrester det vil si alkylrester hvori det ved en indre ringslutning i alkylgruppen dannes et cyklisk system, og som inneholder minst 3 karbonatomer er cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl, cykloheptyl og cyklooktyl som alle også kan være substituert med en eller flere, like eller forskjellige Ci-ralkylrester, særlig metyl. Eksempler på slike cykloalkylrester er 4-metylcykloheksyl, 4-tert-butyl-cykloheksyl eller 2,3-dimetylcyklopentyl.
Eksempler på arylalkylrester det vil si alkylrester som er substituert med en eller flere, for eksempel en, to, tre eller fire, like eller forskjellige arylrester, som for eksempel aryl-Ci-4-alkyl, er benzylrester, fenyletylrester eller indanylrester. I substituerte alkylrester, for eksempel arylalkyl-, hydroksyalkyl- slik som Ci-3-alkyl-OH eller alkoksyalkyl- som Ci-3-alkyl-O-CM-alkyl, kan substituentene være til stede i en hvilken som helst ønsket posisjon.
Hvis ikke annet er sagt, kan fenylrester, naftylrester og heterocykliske rester, for eksempel heteroarylrester, være usubstituert eller kan bære en eller flere, for eksempel en, to, tre eller fire, like eller forskjellige substituenter som kan være i en hvilken som helst ønsket posisjon. Hvis ikke annet er sagt, kan i disse rester for eksempel de substituenter være til stede som er angitt som substituenter for en arylgruppe. En foretrukken serie substituenter som kan være til stede i resten aryl er dannet av substituentene halogen, CM-alkyl, fenyl, CF3, N02, -O-CM-alkyl, Ci-2-alkylendioksy, NH2, -NH-CO-CM-alkyl, -CN, -CO-NH2,-CO-OH, -CO-O-CM-alkyl. Hvis nitrogrupper er til stede som substituenter i forbindelse med formel I, kan totalt kun opptil to nitrogrupper være til stede i molekylene. Hvis fenylrester er til stede som substituenter i for eksempel arylrester som fenylrester og/eller i heterocykliske rester, kan i disse substituenter benzenringen også være usubstituert eller substituert med en eller flere, for eksempel en, to, tre eller fire, like eller forskjellige rester, for eksempel rester fra serien CM-alkyl, halogen, CM-alkoksy, trifluormetyl, cyano, hydroksykarbonyl, (CM-alkoksy)karbonyl, aminokarbonyl, nitro, amino og (CM-alkyl)karbonylamino.
I monosubstituerte fenylrester kan substituenten være i 2-posisjon, 3-posisjon eller 4-posisjon, i disubstituerte fenylrester kan substituentene være i 2,3-posisjon, 2,4-posisjon, 2,5-posisjon, 2,6-posisjon, 3,4-posisjon eller 3,5-posisjon. I trisubstituerte fenylrester kan substituentene være i 2,3,4-posisjon, 2,3,5-posisjon, 2,3,6-posisjon, 2,4,5-posisjon, 2,4,6-posisjon eller 3,4,5-posisjon. Tolyl (= metylfenyl) kan være 2-tolyl, 3-tolyl eller 4-tolyl. Naftyl kan være 1-naftyl eller 2-naftyl. I monosubstituerte 1-naftylrester kan substituenten være i 2-posisjon, 3-posisjon, 4-posisjon, 5-posisjon, 6-posisjon, 7-posisjon eller 8-posisjon, i monosubstituerte 2-naftylrester i 1-posisjon, 3-posisjon, 4-posisjon, 5-posisjon, 6-posisjon, 7-posisjon eller 8-posisjon.
Forklaringene ovenfor så vel som de følgende forklaringer i forbindelse med mono-valente rester har tilsvarende gyldighet for de divalente rester fenylen. De frie bindinger via hvilke de toverdige rester er festet til nabogruppene kan være til stede på et hvilket som helst ringkarbonatom. Når det gjelder en fenylenrest, kan de være i 1,2-posisjon (orto-fenylen), 1,3-posisjon (meta-fenylen) eller 1,4-posisjon (para-fenylen).
Heteroarylrester, heterocykler som representerer ringen A2 og ringer som dannes av to grupper bundet til et nitrogenatom sammen med nitrogenatomet, avledes fortrinnsvis fra heterocykler som inneholder et eller to, like eller forskjellige heteroatomer. Hvis ikke annet er sagt, kan heterocyklene være monocykliske eller bicykliske. Ringene er fortrinnsvis 5-leddede, 6-leddede eller 7-leddede ringer. Eksempler på monocykliske og bicykliske heterocykliske systemer hvorfra restene som opptrer i forbindelsen med formel I kan avledes, er pyrrol, furan, tiofen, imidazol, pyrazol, 1,3-dioksol, 1,3-oksazol, (= oksazol), 1,2-oksazol (= isoksazol), 1,3-tiazol (= tiazol), 1,2-tiazol (= isotiazol), pyridin, pyridazin, pyrimidin, pyrazin, pyran, tiopyran, 1,4-dioksin, 1,2-oksazin, 1,3-oksazin, 1,4-oksazin, 1,2-tiazin, 1,3-tiazin, 1,4-tiazin, azepin, 1,2-diazepin, 1,3-diazepin, l,4diazepin, 1,3-oksazepin, 1,3-tiazepin, indol, benzotiofen, benzofuran, benzotiazol, benzimidazol, kinolin, isokinolin, kinolin, kinazolin, kinoksalin, ftalazin, tienotiofener, 1,8-naftyridin og andre naftyridiner, hver av disse i mettet form (perhydroform) eller i partielt umettet form (for eksempel i dihydroform eller tetrahydroform) eller i maksimalt umettet form, så langt de respektive former er kjente og stabile. Såleds inkluderer heterocykler som er egnet også for eksempel de mettede heterocykler pyrrolidin, piperidin, piperazin, morfolin og tiomorfolin. Graden av mettethet i heterocykliske grupper antydes ved deres individuelle definisjoner. Umettede heterocykler kan for eksempel inneholde en, to eller tre dobbeltbindinger i ringsystemet. 5-leddede ringer og 6-leddede ringer kan særlig også være aromatiske.
Restene som avledes fra disse heterocykler kan være bundet via hvilke som helst egnet karbonatom. Nitrogenheterocykler som kan bære et hydrogenatom eller en substituent på et ringnitrogenatom, for eksempel pyrrol, imidazol, pyrrolidin, morfolin, piperazin, og så videre, kan også være festet via et ringnitrogenatom, særlig hvis den angjeldende heterocykliske rest er bundet til et karbonatom. For eksempel kan en tienylrest være til stede som 2-tienylrest eller en 3-tienylrest, en furylrest som en 2-furyl- eller 3-furylrest, en pyridylrest som en 2-pyridyl-, 3-pyridyl- eller 4-pyridylrest, en piperidinylrest som en 1-piperidnyl- (= piperidinorest), 2-piperidinyl-, 3-piperidinyl- eller 4-piperidinylrest, en (tio)morfolinylrest som 2-(tio)morfolinyl-, 3-(tio)morfolinyl- eller 4-(tio)morfolinyl-rest (= tiomorfolinorest). En rest avledet fra 1,3-tiazol eller imidazol som er bundet via et karbonatom kan være festet via 2-posisjon, 4-posisjon eller 5-posisjon.
Hvis ikke annet er sagt, kan de heterocykliske grupper være usubstituert og kan bære en eller flere, for eksempel en, to, tre eller fire, identiske eller forskjellige substituenter. Substituenter i heterocykler kan være til stede i hvilke som helst ønskede posisjoner, for eksempel i en 2-tienyl- eller 2-furylrest i 3-posisjon og/eller i 4-posisjon og/eller i 5-posisjon, i en 3-tienyl- eller 3-furylrest i 2-posisjon og/eller i 4-posisjon og/eller i 5-posisjon, i en 2-pyridyl- i 3-posisjon og/eller i 4-posisjon og/eller i 5-posisjon og/eller i 6-posisjon, i en 3-pyridylrest i 2-posisjon og/eller i 4-posisjon og/eller i 5-posisjon og/eller 6-posisjon, i en 4-pyridylrest i 2-posisjon og/eller i 3-posisjon og/eller i 5-posisjon og/eller i 6-posisjon. Hvis ikke annet er sagt, kan for eksempel de substituenter være til stede som substituenter i heterocykliske grupper som er antydet i definisjonen for gruppen aryl, og når det gjelder mettede og partielt umettede heterocykler kan som ytterligere substituenter også oksogruppen være til stede. Substituenter på en heterocykel så vel som substituenter på en karbocykel kan også danne en ring, det vil si at det til et ringsystem kan kondenseres ytterligere ringer (eller anelleres) slik at, for eksempel også cyklopenta-kondenserte, cykloheksa-kondenserte eller benzo-kondenserte ringer kan være til stede. Egnede substituenter på et egnet ringnitrogenatom i en heterocykel er særlig for eksempel usubstituerte CM-alkylrester eller arylrester. Egnede nitrogenheterocykler kan også være til stede som N-oksyder eller som kvaternære salter inneholdende et motion som er avledet fra en fysiologisk akseptabel syre. Pyridylrester kan for eksempel være til stede som pyridin-N-oksyder.
Halogen er fluor, klor, brom eller iod, fortrinnsvis fluor eller klor.
Uten å ønske å begrense oppfinnelsen vises det i formlene Ia, le, If, lg og Ih eksempler på grupper av forbindelser ifølge oppfinnelsen, der A<2> i formel I har spesifikke denotasjoner. A<1>, R1, R<2>, R<3>, X og n i formlene Ia, le, If, lg og Di er definert som ovenfor for formel I.
På benzenringen som angitt i formel Ia som bærer gruppene C(=X)-NH og -NHSO2R2 er det til stede fire posisjoner som kan bære en rest R<3>. Forbindelsene med formel Ia kan således bære fire rester R<3> som i henhold til definisjonen av R<3> alle uavhengig av hverandre kan være hydrogen eller ha en betydning forskjellig fra hydrogen, det vil si at i forbindelsene med formel Ia kan benzenringen som angitt i formelen Ia være usubstituert eller kan bære en, to, tre eller fire identiske eller forskjellige substituenter fra serien halogen, CF3, OH, -O-CM-alkyl, -CN, og CM-alkyl. Disse forklaringer gjelder tilsvarende for formlene le til Di.
Foreliggende oppfinnelse inkluderer alle stereoisomere former av forbindelsene med formel I. Asymmetrisentra som er til stede på forbindelsene med formel I kan alle uavhengig av hverandre ha S-konfigurasjon eller R-konfigurasjon. Oppfinnelsen inkluderer alle mulige enantiomerer og diastereomerer og blandinger av to eller flere stereoisomerer, for eksempel blandinger av enantiomerer og/eller diastereomerer, i alle forhold. Således er enantiomerene en gjenstand for oppfinnelsen i enantiomert ren form, både som venstredreiende og høyredreiende antipoder, i form av racemater og i form av blandinger av de to enantiomerer i alle forhold. Når det gjelder en cis/trans-isomeri, omfatter oppfinnelsen både cis-formen og trans-formen så vel som blandinger av disse former i alle forhold. Fremstillingen av individuelle stereoisomerer kan hvis ønskelig, gjennomføres ved separering av en blanding på vanlig måte, for eksempel ved kromatografi eller krystallisering, ved bruken av stereokjemisk enhetlige utgangsstoffer for syntese eller ved stereoselektiv syntese. Eventuelt kan en derivatisering gjennomføres før en separering av stereoisomerer. Separeringen av en blanding av stereoisomerer kan gjennomføres på trinnet for forbindelsene med formel I eller på trinnet på et mellom-produkt under syntesen. Oppfinnelsen omfatter også alle tautomere former av forbindelsene med formel I.
Hvis forbindelsene med formel I inneholder en eller flere sure eller basiske grupper, omfatter oppfinnelsen også de tilsvarende fysiologisk eller toksikologisk akseptable salter, særlig de farmasøytisk brukbare salter. Således kan forbindelser med formel I som inneholder sure grupper være til stede på disse grupper og kan benyttes i henhold til oppfinnelsen, for eksempel som alkalimetallsalter, jordalkalimetallsalter eller ammoniumsalter. Eksempler på slike salter er natrium-, kalium-, kalsium-, magnesium-salter eller salter med ammoniakk eller organiske aminer som etylamin, etanolamin, trietanolamin eller aminosyrer. Forbindelser med formel I som inneholder en eller flere basiske grupper, det vil si grupper som kan protoneres, kan være til stede og kan benyttes i henhold til oppfinnelsen i form av syreaddisjonssalter med uorganiske eller organiske syrer, for eksempel som salter med saltsyre, hydrogenbromsyre og hydro-fosfor-, svovel-, salpeter-, metansulfon-, p-toluensulfon-, naftalendisulfon-, oksal-, eddik-, vin-, melke-, salicyl-, benzo-, maur-, propion-, pivalin-, dietyleddik-, malon-, rav-, pimelin-, furnar-, malein-, malin-, sulfamin-, fenylpropion-, glukon-, askorbin-, isonikotin-, sitron- eller adipinsyre. Hvis forbindelsene med formel I samtidig inneholder sure og basiske grupper i molekylet, omfatter oppfinnelsen også, i tillegg til de nevnte saltformer, indre salter eller betainer (zwitterioner). Salter kan oppnås fra forbindelsene med formel I i henhold til vanlige metoder som velkjente for fagmannen, for eksempel ved kombinasjon med en organisk eller uorganisk syre eller base i et oppløsnings- eller dispergeringsmiddel, eller ved anion- eller kationbytting fra andre salter. Oppfinnelsen omfatter også alle salter av forbindelsene med formel I som, på grunn av lav fysiologisk kompatibilitet, ikke er direkte egnet for bruk i farmasøytika, men som for eksempel kan benyttes som mellomprodukter for kjemiske reaksjoner, eller for fremstilling av fysiologisk akseptable salter.
Oppfinnelsen omfatter videre alle solvater av forbindelser med formel I, for eksempel hydrater eller addukter med alkoholer, og også derivater av forbindelsene med formel I som estere, amider, prodrugs og aktive metabolitter.
Fenylenresten A<1> kan være usubstituert eller kan være substituert som antydet. Hvis gruppen A<1> er substituert, det vil si hvis den bærer en eller flere substituenter i tillegg til gruppen PJ-SCO),,, er den fortrinnsvis substituert med en eller to, like eller forskjellige av de substituenter som er antydet ovenfor. Fortrinnsvis er en fenylenrest som representerer A<1> usubstituert, det vil si at den ved siden av gruppene R<]->S(0)n og C(=X)-NH bærer fire hydrogenatomer. Gruppen R^SCO),, er fortrinnsvis knyttet til et karbonatom i A<1> som ikke direkte er nabo til karbonatomet som bærer gruppen C(=X)-NH. Det vil si R^SCO^ er spesielt foretrukket lokalisert i metaposisjon eller i para-posisjon, aller helst i para-posisjon, med henblikk på karbonatomet som bærer gruppen C(=X)-NH.
Ringen A<2> som omfatter de to karbonatomer som bærer gruppene R<2->S02-NH og C(=X)-NH er fortrinnsvis en aromatisk ring og helst en benzen- eller en tiofenring, aller helst en benzenring, der alle disse ringer kan være usubstituert eller substituert med en eller flere rester R3 som er forskjellige fra hydrogen.
R<1> er fortrinnsvis NR5R<6> eller fenyl og aller helst NR<5>R<6>, der alle disse rester kan være usubstituert eller substituert som antydet og der, som antydet ovenfor, R<1> kan være NR<5>R<6> hvis tallet n i gruppen R^SCO),,- er 2.
Eksempler på R<2> som er aryl det vil si fenyl eller en rest av en monocyklisk 5- eller 6-leddet, aromatisk heterocykel som inneholder et eller to, like eller forskjellige heteroatomer fra serien N, O og S som for eksempel fenyl, tienyl, pyrazolyl, imidazolyl, isoksazolyl, tiazolyl, pyridyl, særlig fenyl eller 2-tienyl, der alle disse rester kan være usubstituert eller substituert som antydet. Fortrinnsvis er arylresten som representerer R<2 >substituert. Hvis en arylrest som representerer R<2> er substituert, er den fortrinnsvis substituert med en, to eller tre, særlig med en eller to, like eller forskjellige substituenter. Substituenter i en arylrest som representerer R<2> er fortrinnsvis substituenter fra serien halogen, CF3, NO2, CN, Ci-4-alkyl og -O-CM-alkyl, aller helst er de valgt blant F, Cl, Br, CF3, N02, -CN, CH3 og -OCH3. Særlig foretrukket er det at en substituert arylrest som representerer R<2> er substituert med Cl, for eksempel med et eller to, og særlig et kloratom.
Ringene som representerer A<2> kan være usubstituerte eller substituerte som antydet. Når de er usubstituerte bærer de kun rester R3 som er hydrogen. Når de er substituerte bærer de en eller flere rester R3 som er forskjellige fra hydrogen. Disse substituentposisjoner som ikke bærer noen rest R<3> som er forskjellig fra hydrogen, bærer hydrogenatomer. Hvis ringen A<2> bærer en eller flere rester R<3> som er forskjellige fra hydrogen, bærer den fortrinnsvis en eller to slike rester R<3>, særlig en slik rest R<3>. Rester R<3> som er forskjellige fra hydrogen er fortrinnsvis lokalisert i posisjoner på ringen A som ikke direkte er nabo til gruppene C(=X)-NH og R<2->S02-NH. Hvis A<2> er en benzenring, er restene R<3 >som er forskjellige fra hydrogen, fortrinnsvis Ci-3-alkyl, halogen, Ci.3-alkoksy eller CF3 og aller helst metyl, klor eller metoksy. Hvis A er en benzenring, er det meget spesielt foretrukket hvis ringen bærer et kloratom eller to metoksygrupper som substituenter, det vil si hvis en rest R3 er til stede som er klor, eller hvis to rester R<3> er til stede som er metoksy, og de andre posisjoner på benzenringen bærer hydrogenatomer. Hvis A er en benzenring, er restene R3 som er forskjellige fra hydrogen, fortrinnsvis lokalisert i 4-og/eller 5-posisjoner (i forhold til gruppen C(=X)-NH i 1-posisjon og gruppen R<2->S02-NH i 2-posisjon).
Med hensyn til R<5> og R<6> er det foretrukket hvis R<5> og R<6> sammen med nitrogenatomet som bærer disse rester, danner en 5-, 6- eller 7-leddet heterocykel som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde et ytterligere ringheteroatom valgt blant N, O og S og som kan være substituert med en eller flere, for eksempel en, to, tre eller fire, like eller forskjellige rester valgt blant Ci-3-alkyl, hydroksy-Ci-3-alkyl-, 5- eller 6-leddet aryl, karbamoyl, hydroksy og okso, særlig Ci-3-alkyl som for eksempel metyl. Fortrinnsvis er en heterocykel som dannes fra gruppene R<5> og R<6> sammen med nitrogenatomet som bærer disse rester, mettet.
Spesielt foretrukket er en heterocykel som dannes av R<5> og R<6> sammen med nitrogenatomet som bærer disse rester, avledet fra morfolin, tiomorfolin, 1,1-diokso-tiomorfolin, 1-okso-tiomorfolin, fra dialkylmorfoliner som dimetylmorfoliner, fra 2,6-dimetylmorfolin, cis-2,6-dimetylmorfolin, 3,5-dimetylmorfolin, cis-3,5-dimetylmorfolin, l-(pyrimidin-2-yl)-piperazin, piperidin-4-karboksamid, l-(2-hydroksyetyl)-piperazin, 1-metyl-piperazin, 1-etylpiperazin, fra 1-arylpiperaziner, fraetylpiperazin-l-karboksylat, piperidin, 2-metylpiperidin, 2,6-dimetylpiperidin, cis-2,6-dimetylpiperidin, 3,5-dimetylpiperidin, cis-3,5-dimetylpiperidin, 4-hydroksypiperidin, fra 4-oksopiperidin eller et ketal derav som l,4-dioksa-8-aza-spiro[4,5]decan, fra tetrahydropyridin, tetrahydro-pyrimidin, 1-metylhomopiperazin, tiazolidin, pyrrolin, pyrrolidin, 3-hydroksypyrrolidin, 1,2,3,4-tetrahydroisokinolin eller 2,3-dihydro-lH-isoindol, der disse ringer er festet via ringnitrogenatomet eller, når det gjelder piperazinderivater, via det usubstituerte ringnitrogenatom. Mer spesielt foretrukket er en heterocykel som er dannet av R<5> og R<6 >sammen med nitrogenatomet som bærer restene, avledet fra morfolin, tiomorfolin, 1,1-diokso-tiomorfolin, 1-okso-tiomorfolin, 2,6-dimetylmorfolin, cis-2,6-dimetylmorfolin, 3,5-dimetylmorfolin, cis-3,5-dimetylmorfolin, l-(pyrimidin-2-yl)-piperazin, piperidin-4- karboksamid, 1,2,3,4-tetrahydroisokinolin eller 2,3-dihydro-lH-isoindol, særlig foretrukket fra morfolin, 2,6-dimetylmorfolin eller cis-2,6-dimetylmorfolin, aller helst fra morfolin eller cis-2,6-dimetylmorfolin, der disse ringer er festet via ringnitrogenatomet eller, når det gjelder piperazinderivatet, via det usubstituerte ringnitrogenatom.
Hvis ikke annet er sagt er foretrukne substituenter på arylrester det vil si på fenyl eller 5- eller 6-leddet heteroaryl, valgt blant halogen, CF3, Ci-3-alkyl, cyano, nitro og C1.3-alkyloksy, helst CF3, klor, metyl og metoksy.
Heteroaryl, det vil si en rest av en monocyklisk 5- eller 6-leddet aromatisk heterocykel, er særlig en rest avledet fra heteroaromatene tiofen, pyrazol, tiazol, oksazol, isoksazol, pyridin, pyrimidin og pyridazin.
Tallet n i gruppen R^SCCOn er fortrinnsvis 2.
Foretrukne forbindelser med formel I er de forbindelser der en eller flere av restene der de har foretrukne betydninger, idet alle kombinasjoner av foretrukne substituentdefini-sjoner er en gjenstand for oppfinnelsen. Med henblikk på alle foretrukne forbindelser med formel I omfatter videre foreliggende oppfinnelse alle stereoisomere former og blandinger derav i alle forhold og deres fysiologisk godtagbare salter. Grupper av foretrukne forbindelser dannes, for eksempel av forbindelsene med formlene Ia, le, If, lg og Hi der en eller flere rester har foretrukne betydninger, i alle sine stereoisomere former og blandinger derav i alle forhold, og deres fysiologisk godtagbare salter.
En gruppe av spesielt foretrukne forbindelser dannes for eksempel ved forbindelser med formel I, der
A<1> er fenylen som er usubstituert eller substituert med en eller flere, like eller forskjellige substituenter valgt blant halogen, CM-alkyl, CF3, -O-CM-alkyl og -CN;
ringen A<2> som omfatter de to karbonatomer som bærer gruppene R<2->S02-NH og C(=X)-NH- er en benzenring;
R1 er NR5R6;
R er aryl;
R3 angir en eller flere, like eller forskjellige rester valgt blant hydrogen, halogen, CF3, -O-CM-alkyl, -CN og CM-alkyl;
R<5> og R<6> sammen med nitrogenatomet som bærer R<5> og R<6> danner en 5- til 6-leddet, mettet heterocykel som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde et ytterligere ringheteroatom, valgt blant N, O og S og som kan være substituert med en eller flere, like eller forskjellige rester valgt blant Ci-3-alkyl, hydroksy-Ci-3-alkyl-, aryl, karbamoyl, hydroksy og okso;
aryl er fenyl eller 5- eller 6-leddet heteroaryl inneholdende et eller flere, like eller forskjellige ringheteroatomer, valgt blant N, O og S, hvilke rester alle kan være substituert med en eller flere, like eller forskjellige substituenter fra serien halogen, CM-alkyl, CF3, N02, -O-CM-alkyl, -NH-CO-CM-alkyl 0g -CN;
ner 2;
X er oksygen;
i alle sine stereoisomere former og blandinger derav i alle forhold, og deres fysiologisk akseptable salter.
En gruppe spesielt foretrukne forbindelser dannes for eksempel av forbindelser med formel I, der
A<1> er en usubstituert, toverdig fenylenrest;
ringen A<2> som omfatter de to karbonatomer som bærer gruppene R<2->S02-NH og C(=X)-NH- er en benzenring;
R1 er NR5R6;
R<2> er aryl;
R<3> angir en eller flere, like eller forskjellige rester valgt blant hydrogen, halogen, -O-CM-alkyl og CM-alkyl;
R<5> og R<6> sammen med nitrogenatomet som bærer R5 og R<6> danner en mettet 6-leddet heterocykel som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde et ytterligere ringheteroatom valgt blant N, O og S og som kan være substituert med en eller flere, like eller forskjellige rester valgt blant Cu-alkyl, aryl, okso og karbamoyl;
aryl er fenyl eller 5- eller 6-leddet heteroaryl inneholdende en eller flere, like eller forskjellige ringheteroatomer valgt blant N, O og S, hvilke rester alle kan være substituert med en eller flere, like eller forskjellige substituenter, valgt blant halogen, CM-alkyl, CF3 og -O-CM-alkyl;
ner 2;
X er oksygen;
i alle sine stereoisomere former og blandinger derav i alle forhold og deres fysiologisk akseptable salter.
En gruppe av de aller mest foretrukne forbindelser dannes for eksempel av forbindelser med formel I, der: A<1> er en usubstituert, toverdig 1,4-fenylenrest;
ringen A<2> som omfatter de to karbonatomer som bærer gruppene R<2->S02-NH og C(=X)-NH- sammen med restene R<3>, er en benzenring som bærer en eller to substituenter valgt blant serien klor og metoksy;
R1 er NR5R6;
R<2> er fenyl eller tienyl, hvilke rester alle er substituert med et eller to kloratomer;
R<5> og R6 sammen med nitrogenatomet som bærer R<5> og R6 danner en mettet 6-leddet heterocykel som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde et ytterligere ringheteroatom valgt blant O og S og som er usubstituert eller substituert med en eller to metylrester;
ner 2;
X er oksygen;
i alle sine stereoisomere former og blandinger derav i alle forhold og deres fysiologisk akseptable salter.
Foreliggende oppfinnelse angår også fremgangsmåter for fremstilling av forbindelsene med formel I som beskrives i det følgende og via hvilke forbindelsene ifølge oppfinnelsen kan oppnås. I henhold til reaksjonsskjema 1 kan forbindelser ifølge oppfinnelsen oppnås for eksempel ved først å omsette en aminokarboksylsyre med formel II med et sulfonylklorid med formel R2-SC>2-C1 eller et sulfonsyreanhydrid i nærvær av en base i et oppløsningsmiddel som vann, pyridin eller en eter. Egnede baser er uorganiske baser som natriumkarbonat og organiske baser er for eksempel pyridin eller trietylamin. Sulfonylaminokarboksylsyren med formel III som oppnås kan så aktiveres, for eksempel ved omsetning med kloreringsmiddel som fosforpentaklorid, fosforoksyklorid eller tionylklorid i et hvilket som helst inert oppløsningsmiddel for derved å gi et syreklorid med formel IV, som så omsettes med et arylamin. Aktiveringen av karboksylgruppen i forbindelsene med formel HI kan imidlertid også gjennomføres på en annen måte, for eksempel ved en av de tallrike metoder for dannelse av aminbindinger i peptidkjemien som er velkjente for fagmannen, for eksempel ved omdanning til et blandet anhydrid eller en aktivert ester eller ved bruk av et karbodiimid som dicykloheksylkarbodiimid. Reaksjonen av den aktiverte sulfonylaminokarboksylsyre med et arylamin gjennom-føres fortrinnsvis i et inert oppløsningsmiddel som pyridin, tetrahydrofuran eller toluen i nærvær eller fravær av en inert hjelpebase, for eksempel det tertiært amin eller pyridin. Hvis arylaminet som benyttes i reaksjonen med den aktiverte karboksylsyre allerede inneholder den ønskede substituent R<1->S(0)n, gir denne reaksjon direkte sluttforbin-delsen med formel I. Forbindelser med formel I der tallet n i gruppen R^SCO),, er 2, kan også oppnås ved omsetning av en aktivert karboksylsyre med et merkapto-substituert arylamin med formelen R<1->S-A<1->NH2 og så oksydere merkaptogruppen i forbindelsen med formel V under standardbetingelser, for eksempel med et peroksyd som hydrogenperoksyd eller en persyre som 3-klorperbenzosyre eller monoperoksyftalsyre i et oppløsningsmiddel som metylenklorid eller aceton. De aktiverte karboksylsyrer kan også først omsettes med arylaminer med formelen A'-NH2. Det resulterende reaksjons-produkt med formel VI kan så klorsulfoneres under standardbetingelser og klorsulfonyl-gruppen kan så omdannes under standardbetingelser til gruppen R<1->S02, for eksempel ved omsetning med egnede aminer i substans eller i et oppløsningsmiddel som N-metyl-pyrrolidon, dimetylformamid, toluen eller en eter, eventuelt i nærvær av en hjelpebase. På samme måte kan de aktiverte karboksylsyrer omsettes med fluorsulfonylarylaminer med formel F-S02-A<1->NH2 og fluorsulfonylmellomproduktene med formel VII som oppnås kan omdannes under standardbetingelser til forbindelser med formel I ifølge oppfinnelsen.
Forbindelsene med formel I ifølge oppfinnelsen kan videre oppnås ved omsetning av de aktiverte sulfonylaminokarboksylsyre, for eksempel med syreklorider med formel IV som vist i skjema 1, med et merkaptoarylamin med formelen H^N-A^SH som er usubstituert på svovelatomet. I en nukleofil substitusjonsreaksjon kan produktet med formel VIII som her oppnås, deretter alkyleres eller aryleres på svovelatomet med et alkyl-halogenid eller et arylhalogenid eller en annen reaktiv forbindelse under standardbetingelser og, hvis ønskelig, oksyderes på svovelet for å gi sulfonet som forklart ovenfor med henblikk på forbindelser med formel V (se skjema 2).
Forbindelser med formel I kan også oppnås, for eksempel ved først å aktivere en egnet substituert nitrokarboksylsyre med formel IX, for eksempel ved omdanning av denne til det respektive syreklorid med formel X eller ved en annen prosedyre, og så omsetning med et egnet arylamin med formelen R<1->S(0)n-A<1->NH2 analogt de prosedyrer som er beskrevet ovenfor (se skjema 3). Også her kan man som arylaminer benytte fluorsulfonylarylaminer med formelen F-S02-A<1->NH2, og i N-(fluorsulfonylaryl)-karboks-amidene med formel XI som oppnås, kan fluorsulfonylgruppen omdannes under standardbetingelser til en gruppe R'-S02 i henhold til oppfinnelsen, for eksempel med et amin med formelen HNR<5>R<6>.
Før nitrogruppene i nitromellomproduktene med formel XII som oppnås, reduseres til en aminogruppe, kan man benytte den aktiverende effekt av nitrogruppen på ringen A og en egnet rest R , for eksempel et halogenatom, kan erstattes med en annen rest R ved omsetning med en nukleofil, for eksempel et amin. Reduksjonen av nitrogruppen for å gi en aminogruppe kan for eksempel gjennomføres ved katalytisk hydrogenering i nærvær av en edelmetallkatalysator eller, fortrinnsvis, i nærvær av Raney-nikkel i et oppløsningsmiddel som etanol, iseddik eller en etanolisk oppløsning av hydrogenklorid, eller den kan gjennomføres ved omsetning av et basemetall som sink, tinn eller jern i nærvær av en syre. Reduksjonen kan også gjennomføres for eksempel med tinn(II)-klorid eller ved omsetning med natriumditionitt, fortrinnsvis i en blanding av metanol, tetrahydrofuran og vann som oppløsningsmiddel. Sulfonyleringen av aminogruppen i reaksjonsproduktet med formel XIII med et aktivert sulfonylsyrederivat kan gjennom-føres analogt reaksjonene som beskrevet ovenfor, for eksempel med et sulfonsyreklorid i pyridin, noe som til slutt gir forbindelsen med formel I. Alle reaksjoner for syntesen av forbindelsene med formel I er per se velkjente for fagmannen og kan gjennomføres under standardbetingelser i henhold til eller analogt med prosedyrer som er beskrevet i litteraturen, for eksempel i Houben-Weyl, "Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, eller "Organic Reactions", John Wiley & Sons, New York. Avhengig av omstendighetene i det enkelte tilfelle og for å unngå bireaksjoner under syntesen av en forbindelse med formel I kan det være nødvendig eller fordelaktig temporært å blokkere funksjonelle grupper ved å innføre beskyttende grupper og å avbeskytte disse på et senere trinn i syntesen, eller å innføre funksjonelle grupper i form av forløpergrupper som i et senere reaksjonstrinn omdannes til den ønskede, funksjonelle gruppe. Slike syntetiske strategier og beskyttende grupper omfatter forløpergrupper som er egnet i et individuelt tilfelle er kjent for fagmannen. Hvis ønskelig kan forbindelsene med formel I også renses ved vanlige renseprosedyrer, for eksempel ved omkrystallisering eller kromatografi. Utgangsforbindelsene for fremstilling av forbindelsene med formel I er kommersielt tilgjengelige eller kan fremstilles i henhold til eller i analogi med litteraturprosedyrer.
Forbindelsene med formel I ifølge oppfinnelsen bevirker en økning av cGMP-konsentrasjonen via aktiveringen av den oppløselige guanylatcyklase og de er derfor brukbare midler for terapi og profylakse av mangler som er assosiert med et lavt eller redusert cGMP-nivå, eller som er forårsaket av dette, eller for visse terapi eller profylakse en økning av det øyeblikkelige cGMP-nivået er ønsket. Aktiveringen av sGC med forbindelser med formel I kan undersøkes for eksempel i den aktivitetsanalyse som er beskrevet nedenfor.
Mangler og patologiske tilstander som er forbundet med et lavt cGMP-nivå eller der en økning av cGMP-nivået er ønskelig, og for hvis terapi og profylakse det er mulig å benytte forbindelser med formel I, er for eksempel kardiovaskulære sykdommer som endotelial dysfunksjon, diastolisk dysfunksjon, aterosklerose, hypertensjon, stabil og ustabil angina pectoris, tromboser, restenoser, myokardialt infarkt, slag, kardial insuffisiens eller pulmonær hypertoni eller, for eksempel erectil dysfunksjon, astma bronkiale, kronisk nyreinsuffisiens og diabetes. Forbindelser med formel I kan i tillegg benyttes ved terapi av cirrhose i leveren og også for å forbedre en begrenset hukommelsesytelse eller læreevne.
Forbindelsene med formel I og deres fysiologisk akseptable salter kan administreres til dyr, fortrinnsvis pattedyr, og særlig til mennesker, som farmasøytika per se, eller i blandinger med et annet eller i form av farmasøytiske preparater. En gjenstand for oppfinnelsen er derfor også forbindelser med formel I og deres fysiologisk akseptable salter for bruk som farmasøytika, deres anvendelse for fremstilling av medikamenter for å aktivere oppløselig guanylatcyklase, for normalisering av en forstyrret cGMP-balanse og særlig deres anvendelse i terapi og profylakse av de ovenfor nevnte syndromer. Videre er en gjenstand for oppfinnelsen farmasøytiske preparater (eller farmasøytiske blandinger) som omfatter en eller flere forbindelse med formel I og/eller deres fysiologisk akseptable salter og en vanlig farmasøytisk akseptabel bærer, det vil si en eller flere farmasøytisk akseptable bærestoffer og/eller additiver.
Oppfinnelsens farmasøytika kan administreres oralt, for eksempel i form av piller,
tabletter, lakkerte tabletter, sukkerbelagte tabletter, granuler, hårde og myke gelatin-kapsler, vandige, alkoholiske eller oljeoppløsninger, siruper, emulsjoner eller suspen-sjoner, eller rektalt, for eksempel i form av suppositorier. Administreringen kan også gjennomføres parenteralt, for eksempel subkutant, intramuskulært eller intravenøst i form av oppløsninger for injeksjon eller infusjon. Andre egnede administreringsformer er for eksempel perkutan eller topisk administrering, for eksempel i form av salver, tinkturer, sprayer eller transdermale terapeutiske systemer, eller den inhalative administrering i form av nasalspray eller aerosolblandinger, eller for eksempel mikrokapsler, implantater eller staver. Den foretrukne administreringsform avhenger av sykdommen som skal behandles og dennes alvor.
Mengden aktiv forbindelse med formel I og/eller dens farmasøytisk akseptable salter i de farmasøytiske preparater er vanligvis fra 0,2 til 500 mg, fortrinnsvis fra 1 til 200 mg, pr. dose, men avhengig av typen farmasøytisk preparat kan den også være høyere. De farmasøytiske preparater omfatter vanligvis 0,5 til 90 vekt-% av forbindelsene med formel I og/eller deres fysiologisk akseptable salter. Fremstillingen av de farmasøytiske preparater kan gjennomføres på i og for seg kjent måte. For dette formål bringes en eller flere forbindelser med formel I og/eller deres fysiologisk akseptable salter, sammen med ett eller flere faste eller flytende farmasøytisk bærestoffer og/eller additiver (eller hjelpestoffer) og, hvis ønskelig, i kombinasjon med andre farmasøytisk aktive forbindelser med terapeutisk eller profylaktisk virkning, til en egnet administreringsform eller doseform som så kan benyttes som farmasøytikum i human- eller veterinærmedisinen.
For produksjonen av piller, tabletter, sukkerbelagte tabletter og hårdgelatinkapsler er det for eksempel mulig å bruke lactose, stivelse som maisstivelse, eller stivelsesderivater, talkum, stearinsyre eller dennes salter. Bærere for mykgelatinkapsler og suppositorier er for eksempel fett, vokser, halvfaste og flytende polyoler, naturlige eller herdede oljer, og så videre. Egnede bærere for fremstillingen av oppløsninger, for eksempel oppløs-ninger for injeksjon, eller av emulsjoner eller siruper, er for eksempel vann, fysiologisk natriumkloridoppløsning, alkoholer som etanol, glycerol, polyoler, sucroser, invert sukker, glucose, mannitol, vegetabilske oljer, og så videre. Det er også mulig å lyofili-sere forbindelsene med formel I og deres fysiologisk akseptable salter og å bruke de resulterende lyofilisater, for eksempel for fremstilling av preparater for injeksjon eller infusjon. Egnede bærere for mikrokapsler, implantater eller staver er, for eksempel kopolymerer av glycolsyre og melkesyre.
Ved siden av de aktive forbindelser og bærere, kan de farmasøytiske preparater også inneholde vanlige additiver som fyllstoffer, disintegratorer, bindemidler, smøremidler, fuktemidler, stabilisatorer, emulgatorer, dispergeringsmidler, preserveringsmidler, søtnere, farvestoffer, smaksstoffer, aromagivende midler, fortykkere, fortynningsmidler, bufferstoffer, oppløsningsmidler, oppløseliggjørende midler, midler for å oppnå en depotvirkning, salter for å endre det osmotiske trykk, belegningsmidler eller antioksy-danter.
Doseringen av den aktive forbindelse med formel I som skal administreres og/eller av et fysiologisk akseptabelt salt derav, avhenger av det individuelle tilfellet og må, som vanlig, tilpasses de individuelle omstendigheter for å oppnå en optimal virkning. Således avhenger det av arten og alvoret av mangelen som skal behandles, og kjønn, alder, vekt og individuell respons hos mennesket eller dyret som skal behandles, effek-tiviteten og varighet av virkningen av den benyttede forbindelse, eller hvorvidt terapien er akutt, kronisk eller profylaktisk, eller av hvorvidt andre aktive forbindelser administreres i tillegg til forbindelsene med formel I. Generelt vil en daglig dose på rundt 0,01 til 100 mg/kg, fortrinnsvis 0,1 til 10 mg/kg, særlig 0,3 til 5 mg/kg (i hvert tilfelle mg/kg kroppsvekt) være egnet for administrering til en voksen person med en vekt rundt 75 kg for å oppnå de ønskede resultater. Den daglige dose kan administreres i en enkelt dose eller, særlig når større mengder administreres, deles i flere, for eksempel to, tre eller fire individuelle doser. I enkelte tilfelle og avhengig av den individuelle respons, kan det være nødvendig å gå oppover eller nedover fra enhver gitt daglig dose.
Forbindelsene med formel I aktiverer den oppløselige guanylatcyklase, hovedsakelig ved binding i heme-bindingslommen av enzymet. På grunn av denne egenskap og bort-sett fra bruken som farmasøytisk aktiv forbindelse i human- og veterinærmedisinen, kan de også benyttes som et vitenskapelig verktøy eller som hjelpemiddel for biokjemiske undersøkelser, der en slik virkning på guanylatcyklase er tilsiktet, og også for diagno-stiske formål, for eksempel ved in vitro-diagnose av celleprøver eller vevprøver.
Forbindelsene med formel I og salter derav kan videre benyttes som allerede nevnt som mellomprodukter for fremstilling av andre farmasøytisk aktive forbindelser.
De følgende eksempler på forbindelser med formel I og mellomprodukter for deres fremstilling skal illustrere oppfinnelsen uten å begrense den.
Eksempler
1. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzosyre
33,71 g (0,32 mol) natriumkarbonat ble oppløst i 250 ml vann og oppvarmet til 60°C. 25,00 g (0,13 mol) 2-amino-4,5-dimetoksy-benzosyre ble innført i oppløsningen og til oppløsningen ble det satt 29,55 g (0,14 mol) 4-klor-benzensulfonylklorid porsjonsvis over 15 minutter. Efter avkjølingen ble blandingen filtrert under sug, resten ble tatt opp i 1% natriumhydrogenkarbonatoppløsning, hvoretter oppløsningen ble filtrert og produktet precipitert ved tilsetning av IN saltsyre. Det ble oppnådd 15,90 g (55%) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzosyre med smeltepunkt 212-214°C.
På analog måte ble det fremstilt:
2. ) 5>klor-2-(4-klor-fenylsulfonylamino)-benzosyre med smeltepunkt 210°C
3. ) 5-klor-2-(3,4-diklor-fenylsulfonylamino)-benzosyre
6. ) 2-(4-klor-fenylsulfonylamino)-5-metyl-benzosyre med smeltepunkt 201°C
7. ) 3-(4-klor-fenylsulfonylamino)-tiofen-2-karboksylsyre med smeltepunkt 180°C
8. ) 3-(4-klor-fenylsulfonylamino)-pyrazol-4-karboksylsyre, olje
9. ) 2-(4-klor-fenylsulfonylamino)-pyridin-3-karboksylsyre med smeltepunkt (dek.) > 360°C.
10. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzoylklorid
25,90 g (0,07 mol) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzosyre ble blandet med 75 ml toluen. 17,30 g (0,08 mol) fosforpentaklorid ble tilsatt og blandingen omrørt ved 40-45°C i 2,5 timer. Derefter ble blandingen konsentrert under vakuum til halv-parten av sitt volum og det precipiterte produkt ble filtrert av under sug og vasket med en liten mengde toluen. Det ble oppnådd 25,30 g (93%) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzoylklorid med smeltepunkt 175-177°C.
Analogt ble det oppnådd:
11. ) 5-klor-2-(4-klor-fenylsulfonylamino)-benzoylklorid med smeltepunkt 127°C
12. ) 5-klor-2-(3,4-diklor-fenylsulfonylamino)-benzoylklorid med smeltepunkt 117°C 14. ) 2-(4-klor-fenylsulfonylamino)-5-metyl-benzoylklorid med smeltepunkt 114°C 15. ) 3-(4-klor-fenylsulfonylamino)-tiofen-2-karboksylsyreklorid med smeltepunkt 122°C 16. ) 3-(4-klor-fenylsulfonylamino)-pyrazol-4-karboksylsyreklorid med smeltepunkt 260°C
17. ) 2-(4-klor-fenylsulfonylamino)-pyridin-3-karboksylsyreklorid
18. ) 4-((2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzoyl)-amino)-benzen-sulfonylfluorid
10,00 g (25,6 mmol) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzoylklorid ble blandet med 300 ml toluen, 4,49 g (25,6 mmol) 4-aminobenzensulfonylfluorid ble tilsatt og blandingen ble oppvarmet under tilbakeløp i 4 timer. Efter avkjøling ble de precipiterte faststoffer filtrert av under sug og vasket med toluen. Det ble oppnådd 11,71 g (87%) av tittelforbindelsen med et smeltepunkt på 216-219°C.
På analog måte ble det oppnådd:
19. ) 4-((5-2-(4-klor-fenylsulfonylamino)-benzoyl)-amino)-benzensulfonylfluorid med smeltepunkt 242°C 20. ) N-(4-aminosulfonyl-fenyl)-5^ smeltepunkt 260°C 21. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-((4-(4-nitrofenyl)-merkapto)-fenyl)-benzamid med smeltepunkt 255°C 22. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(fenylmerkapto)-fenyl)-benzamidmed smeltepunkt 169°C 23. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-metylmerkapto-fenyl)-benzamid med smeltepunkt 220°C 26.) 4-((5-klor-2-(4-klor-fenylsulfonylamino)-benzoyl)-amino)-benzensulfonylfluorid med smeltepunkt 232°C 28. ) 4-((2-(4-klor-fenylsulfonylamino)-5 -metyl-benzoyl)-amino)-benzensulfonyl-fluorid med smeltepunkt 224°C 29. ) 4-((3-(4-klor-fenylsulfonylamino)-tiofen-2-karbonyl)-amino)-benzensulfonyl-fluorid med smeltepunkt 255°C 30. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-merkapto-fenyl)-benzamidmed smeltepunkt 202°C 31. ) 4-((3-(4-klor-fenylsulfonylamino)-pyrazol-4-karbonyl)-amino)-benzensulfonyl-fluorid med smeltepunkt 251°C 32. ) 3-((5-klor-2-(4-klor-fenylsulfonylamino)-benzoyl)-amino)-benzensulfonylfluorid med smeltepunkt 224°C 33. ) 4-(2-(4-klor-fenylsulfonylamino)-pyridin-3-karbonyl)-amino)-benzensulfonyl-fluorid med smeltepunkt 263-265°C
35. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(2-metylmerkapto-fenyl)-benzamid
36. ) 5-klor-2-(4-klor-fenylsulfonyl)-N-(3-metylmerkapto-fenyl)-benzamid
38. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(4-nitro-fenylsulfonyl^ benzamid 39. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(5-etylsulfonyl-2-hydroksyfenyl)-benzamid
40. ) N-(3-butylsulfamoyl-fenyl)-5-klor-2-(4-klor-fen^
41. ) 5 -klor-2-(4-klor-fenylsulfonylamino)-N-(2-nitro-5 -propylmerkapto-fenyl)-benzamid
44.) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(2-fenylmerkapto-fenyl)-benzam
46.) N-(5-butylsulfamoyl-2-metoksy-fenyl)-5-klor-2-(4-klor-fenylsulfonylamino)-benzamid 48.) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(2-klor-4-metylsulfonylfenyl)-b
51. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(2-sulfamoyl-fenyl)-benzami
52. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(2-metylm benzamid
53. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(3-metylsulfonyl-fenyl)-benzamid
58. ) 5-klor-2-(3,4-diklor-fenylsulfanylamino)-N-(4-etylmerkapto-fenyl)-benzamid med smeltepunkt 171°C 59. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid
500 mg (0,95 mmol) av 4-((2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzoyl)-amino)-benzensulfonylfluorid ble oppløst i 1 ml tiomorfolin og oppvarmet til 90°C i 30 minutter. For opparbeiding ble blandingen helt i 50 ml is/lN saltsyre, precipitatet ble filtrert av under undertrykk, tørket i et vakuumtørkekammer over fosforpentoksyd og så
omkrystallisert fra heksan:etylacetat. Det ble oppnådd 378 mg (65%) av tittelforbindelsen med et smeltepunkt på 241°C.
Analogt ble det oppnådd:
60. ) 2-(4-klor-fenylsulfonyIamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-pyridin-3-karboksamid med smeltepunkt 256-258°C 61. ) N-(4-(4-karbamoyl-piperidin-1 -sulfonyl)-fenyl)-2-(4-klor-fenylsulfonylamino)-pyridin-3-karboksamid med smeltepunkt 273-276°C 62. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(piperidin-l-sulfonyl)-fenyl)-pyridin-3-karboksamid med smeltepunkt 180-183°C 63. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(4-metyl-piperazin-1 -sulfonyl)-fenyl)-benzamid med smeltepunkt 246°C 64. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(4-metyl-piperazin-1 -sulfonyl)-fenyl)-benzamid med smeltepunkt 219°C 65. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 259°C 66. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 251°C 67. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(4-hydroksy-piperidin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 255°C 68. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(l,4-dioksa-8-aza-spiro[4,5]decan-8-sulfonyl)-fenyl)-benzamid med smeltepunkt 256°C 69. ) 5-klor-2-(3,4-diklor-fenylsulfonylamino)-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 253°C 70. ) 5-klor-2-(3,4-diklor-fenylsulfonylamino)-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 222°C 71. ) 5-klor-2-(3,4-diklor-fenylsulfony^ fenyl)-benzamid med smeltepunkt 246°C 72. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 172°C 73. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(4-(2-hydroksy-etyl)-piperazin-1 - sulfonyl)-fenyl)-benzamid med smeltepunkt 277°C 75. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-dietylsulfamoyl-fenyl)-benzamidmed smeltepunkt 226°C 76. ) 5 -klor-2-(4-klor-fenylsulfonylamino)-N-(4-(pipeirdin-1 -sulfonyl)-fenyl)-benzamid med smeltepunkt 240°C 77. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(2-metoksy-etylsulfamoyl)-fenyl)-benzamid med smeltepunkt 209°C 78. ) 2-(4-klor-fenylsulfonylamino)-5-metyl-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 203°C 79. ) 3-(4-klor-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-tiofen-2-karboksamid med smeltepunkt 220°C 80. ) 3-(4-klor-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-lH-pyrazol-4-karboksamid, olje 81. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(3-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 238°C 82. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(3-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 202°C 83. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(3-(4-metyl-piperazin-l-sulfonyl)-fenyl)-benzamidhydroklorid med smeltepunkt 245°C 84. ) 3-(4-klor-fenylsulfonylamino)-N-(4-(tiomorfolin-4-sulfonyl)-fen karboksamid med smeltepunkt 229°C 85. )5-klor-2-(4-klor-fen<y>lsulfon<y>lammo)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 228°C 86. ) 2-(4-klor-fenylsulfonylamino)-5-metyl-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 234°C 87. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(4-metyl-piperazin-1 - sulfonyl)-fenyl)-benzamid med smeltepunkt 172°C 88. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 208°C 89. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(4-hydroksy-piperidin-l-sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 244°C 90. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(piperdin-3-sulfonyl)-fenyl)-benzamid med smeltepunkt 258°C 91. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(tiazolidin-3-sulfonyl)-fenyl)-benzamid med smeltepunkt 261°C 92. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(2,5-dihydro-lH-pyrrol-l-sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 262°C 93. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(l,2,3,6-tetrahydro-pyridin-l-sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 252°C 94. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(2-metyl-piperidin-1 - sulfonyl)-fenyl)-benzamid med smeltepunkt 227°C 95. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(piperazin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 243°C 97. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(4-metyl-piperidin^ sulfonyl)-fenyl)-benzamid med smeltepunkt 267°C 98. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(4-metyl-perhydro-[l,4]-diazepin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 274°C 99. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(4-etyl-piperazin-1 -sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 191°C
101. ) 2-(4-klor-fenylsulfonylamino)-N-(4-( 1,4,5,6-tetrahydro-pyirmidin-1 -sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt dek. > 237°C
102. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(4-(pyrimidin-2-yl)-piperazin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt dek. >194°C
103. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(4-(4-klor-fenyl)-piperazin-1 -sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt dek. >243°C
104. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(indan-l-ylsulfamoyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 161°C
105. ) 2-(4-klor-fenylsulfonylamino)-N-(4-((2-(lH-indol-3-yl)-etyl)-metyl-sulfamoyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 182°C
106. ) 1 -(4-((2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzoyl)-amino)-fenyl-sulfonyl)-piperidin-4-karboksamid med smeltepunkt 252°C
107. ) 2-(4-klor-fenylsulfonylamino)-N-(4-cyklopropylsulfamoyl-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 222°C
108. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(3-hydroksy-pyrrolidin-l-sulfonyl)-fenyl)-4,5-dimetoksy-benzamid med smeltepunkt 272°C
109. )N-(4-(allyl-cykloheksyl-sulfamoyl)-fenyl)-2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-benzamid med smeltepunkt 182°C
110. ) 1 -(4-((2-(4-klor-fenylsulfonylamm^
sulfonyl)-pyrrolidin-2-karboksylsyre med smeltepunkt 240°C (sintring)
111. ) 5-klor-2-nitro-benzoylklorid
100,00 g (0,50 mol) 5-klor-2-nitrobenzosyre ble blandet med 72,20 g (0,61 mol) tionylklorid og blandingen ble oppvarmet under tilbakeløp i 2 timer. Overskytende tionylklorid ble fjernet under vakuum. Det ble oppnådd 106,50 g (ca. 98%) uren 5-klor-2-nitrobenzoylklorid som en olje.
På analog måte ble det oppnådd:
112. ) 5-metyl-2-nitro-benzoylklorid, olje
113. ) 4-(5-klor-2-nitro-benzoylamino)-benzensulfonylfluorid
86,00 g (0,39 mol) 5-klor-2-nitro-benzoylklorid ble oppløst i 300 ml toluen, en oppløs-ning av 62,00 g (0,35 mol) 4-aminobenzensulfonylfluorid ble tilsatt dråpevis og blandingen ble oppvarmet under tilbakeløp i 4 timer. Deretter ble den avkjølt, konsentrert under vakuum til det halve volum, avkjølt og det precipiterte faststoff ble filtrert av under sug. Det ble oppnådd 121,60 g (86%) av tittelforbindelsen med et smeltepunkt på 182-184°C.
På analog måte ble det oppnådd:
114. ) 4-(5-metyl-2-nitro-benzoylamino)-benzensulfonylfluoridmed smeltepunkt 179°C
115. ) 5-klor-N-(4-etylmerkapto-fenyl)-2-nitro-benzamid
116. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-nitro-benzamid
120,00 g (0,33 mol) 4-(5-klor-2-nitro-benzoylamino)-benzensulfonylfluorid, 29,10 g (0,33 mol) morfolin og 33,85 g (0,33 mol) trietylamin ble omrørt i 1200 ml toluen ved 60°C i 2 dager. De precipiterte faststoffer ble filtrert av under sug og omkrystallisert fra aceton:n-heksan. Det ble oppnådd 102,10 g (71%) av tittelforbindelsen med smeltepunkt 243-245°C.
På analog måte ble det oppnådd:
117. ) 5-klor-2-nitro-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt
120°C
118. ) 5-metyl-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-nitro-benzamid med smeltepunkt
249°C
119. ) N-(4-(morfolin-4-sulfonyl)-fenyl)-5-(morfolin-4-yl)-2-nitro-benzamid
20,00 g (0,56 mol) 4-(5-klor-2-nitro-benzoylamino)-benzensulfonylfluorid i 48,5 g (0,557 mol) morfolin ble oppvarmet under tilbakeløp i 1 time. Deretter ble blandingen avkjølt, helt på is:saltsyre og filtrert under sug. Det ble oppnådd 26,0 g (98%) av tittelforbindelsen med smeltepunkt 252°C.
120. ) 2-amino-5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid
11,10 g (26,1 mmol) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-nitro-benzamidble oppløst i 440 ml tetrahydrofuran:metanol 1:1 og en oppløsning av 27,23 g (156,4 mmol) natriumditionitt i 330 ml vann ble tilsatt dråpevis. Etter omrøring i 1 time ved romtemperatur ble de organiske oppløsninger fjernet i en rotasjonsfordamper og det precipiterte produkt filtrert av med sug og renset kromatografisk over silika med metylenklorid:metanol 9:1. Det ble oppnådd 5,68 g (55%) av tittelforbindelsen med smeltepunkt 229-231°C.
På analog måte ble det oppnådd:
121. ) 2-amino-5-klor-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt
177°C
122. ) 2-amino-N-(4-(morfolin-4-sulfonyl)-fenyl)-(5-morfolin-4-yl)-benzamid med
smeltepunkt 228°C
123. ) 2-amino-5-klor-N-(4-etylsulfonyl-fenyl)-benzamidmed smeltepunkt 159-161°C
124. ) 5-klor-2-(5-klor-1,3-dimetyl-1 H-pvrazol-4-sulfonyl-amino)-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid
250 mg (0,60 mmol) 2-amino-5-klor-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid ble oppløst i 10 ml tørr pyridin og en oppløsning av 195 mg (0,85 mmol) 5-klor-l,3-dimetyl-lH-pyrazol-4-sulfonylklorid i 5 ml pyridin ble satt dråpevis til ved 0°C. Efter 2 timer ble blandingen helt på is, precipitert faststoff filtrert av under sug og renset ved kromatografi over silika med metylenklorid:metanol 98:2. Det ble oppnådd 150 mg (69%) av tittelforbindelsen med et smeltepunkt på 215-216°C.
På analog måte ble det oppnådd:
125. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-(4-metyl-fenylsulfonylamino)-benzamid med smeltepunkt 214°C
126. ) 5-klor-2-(3,4-dimetoksy-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 245°C
128. ) 2-((4-acetylamino-fenyl)-sulfonylamino)-5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 198°C
129. ) 5-klot-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 112°C
130. ) 5-klor-2-(5-klor-l,3-dimetyl-pyrazol-4-sulfonyl-amino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 161°C
131. ) 5-klor-2-((l-metyl-imidazol-4-sulfonyl)-amino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 141°C
132. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-(pyridin-3-sulfonylamino)-benzamid
med smeltepunkt 222°C
135.) 2-((2-acetamido-4-metyl-tiazol-5-sulfonyl)-amino)-5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 257°C
136. ) 5-klor-N-(4-(morfolin-4-sulfon
med smeltepunkt 216°C
137. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-(4-trifluormetyl-fenylsulfony
benzamid med smeltepunkt 264°C
138. ) 2-(4-brom-fenylsulfonylamino)-5 -klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 232°C
139. ) 2-(3,5-bis-1rifluormetyl-fenylsulfonylamino)-5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 209°C
140. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-(4-nitro-fenylsulfonylamino)-benzamid med smeltepunkt 239°C
141. ) 5-klor-2-(4-cyano-fenylsuIfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 238°C
143.) 5 -klor-2-(4-isopropyl-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 105°C
145. ) 5-klor-2-(4,5-dibrom-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 232°C
146. ) 5-klor-2-(4-fluor-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 245°C
148.) 5-klor-2-(3-klor-4-metoksy-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 274°C
150. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-(2,4,6-trimetyl-fenylsulfonylamino)-benzamid med smeltepunkt 240°C
151. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-(3-nitro-fenylsulfonylamino)-benzamid med smeltepunkt 220°C
152. ) 5-klor-2-(4-metoksy-fenylsulfonylamino)-N-(4-(morfolin-4-sulfon
benzamid med smeltepunkt 269°C
153. ) 5-klor-2-metylsulfonylamino-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med
smeltepunkt 248°C
157. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-2-(3-tirfluormetyl-fenylsulfonylamino
benzamid med smeltepunkt 212°C
158. ) 2-(4-brom-2,5-diklor-tiofen-2-sulfonylamino)-5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 267°C
159. ) 5-klor-N-(4-(morfolin-4-sulfonyl)-feny
benzamid med smeltepunkt 234°C
160. ) 5-klor-2-(3-klor-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid
med smeltepunkt 206°C
161. ) 2-(4-brom-2-metoksy-fenylsulfonylamino)-5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 260°C
162. ) 5-klor-2-(2,6-diklor-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 244°C
163. ) 5-klor-2-(2-cyano-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 200°C
164. ) 2-(4-butoksy-fenylsulfonylamino)-5-klor-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 225°C
166.) 5-klor-2-(3-fluor-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 204°C
168.) 5-klor-N-(4-etylsulfonyl-fenyl)-2-(4-metyl-fenylsulfonylamino)-benzamid med smeltepunkt 188-192°C
169. ) 5-klor-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-etylsulfonyl-fenyl)-ber^ med
smeltepunkt 195-197°C
170. ) 5-klor-2-(4-klor-3-nitro-fenylsulfonylamino)-N-(4-etylsulfonyl-fenyl)-benzamid
med smeltepunkt 196-198°C
171. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-etylsulfonyl-fenyl)-benzamid med
smeltepunkt 180-185°C
172. ) 5-klor-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-etylsulfonyl-fenyl)-benzamid med smeltepunkt dek. > 249°C
175. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(l, 1 -diokso-tiomorfolin-4-sulfonyl)-fenyl)-benzamid
176. ) 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(l-okso-tiomorfolin-4-sulfonyl)-fenyl)-benzamid
500 mg (0,82 mmol) av 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid i 50 ml aceton ble avkjølt til 0°C. En oppløsning av 371 mg (1,23 mmol) 57 %-ig m-klorperbenzosyre i 20 ml aceton ble tilsatt og blandingen omrørt ved romtemperatur over natten. For opparbeiding ble den helt på vann:is og precipitatet filtrert av under sug. De to produkter som ble oppnådd som en blanding ble separert ved kromatografi over silika med metylenklorid:metanol 97:3.
På analog måte ble det oppnådd:
177. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(l,l-diokso-tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 182°C
178. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(l-okso-tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 233°C
179. ) 5-klor-2-(3,4-diklor-fenylsulfonylamino)-N-(4-etylsulfonyl-fenyl)-benzamid med
smeltepunkt 240°C
180. ) 5-klor-N-(4-etylsulfonyl-fenyl)-2-nitro-benzamid
183.) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-isopro^
1,00 g (2,21 mmol) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-merkapto-fenyl)-benzamid ble oppløst i 25 ml dimetylformamid og 0,25 g (2,21 mmol) kalium-tert-butylat ble tilsatt. Blandingen ble omrørt ved romtemperatur i 15 minutter og deretter ble 0,27 g (2,21 mmol) isopropylbromid tilsatt dråpevis, hvoretter blandingen ble oppvarmet til 60°C i 8 timer. For opparbeiding ble den helt på vann og ekstrahert med etylacetat. De kombinerte ekstrakter ble fordampet og resten renset ved kromatografi over silika med heksametylacetat 3:1. Det ble oppnådd 420 mg (39%) av tittelforbindelsen med smeltepunkt 168-169°C.
190. ) 5-klor-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid.natriumsalt
En blanding av 0,48 g finpulverisert natriumhydroksyd og 7 g 5-klor-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid i 150 ml etanol ble bragt i oppløsning ved kort oppvarming. Deretter ble blandingen fordampet under vakuum, 50 ml vann ble tilsatt og det hele igjen fordampet under vakuum til tørr tilstand. Denne prosedyre ble gjentatt to ganger. Det resulterende produkt ble tørket under vakuum ved 50°C, smeltepunktet var 343°C (dek.).
Analogt de ovenfor angitte forbindelser ble følgende eksempelforbindelser oppnådd: 191. ) 4,5-dimetoksy-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(N-metyl-N-(pyridin-3-yl-metyl)-aminosulfonyl)-fenyl)-benzamidhydroklorid med smeltepunkt 214°C
192. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(morfolin-4-sulfonyl)-3-metyl-fenyl)-benzamid med smeltepunkt 192°C
193. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-cis-2,6-dimetyl-morfolin-4-sulfonyl)-3-metyl-fenyl)-benzamid med smeltepunkt 254°C
194. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(3,5-dimetyl-piperidin-l-sulfonyl)-3-metyl-fenyl)-benzamid med smeltepunkt 242°C
195. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(piperidin-l-sulfonyl)-3-metyl-fenyl)-benzamid med smeltepunkt 189°C
196. ) 4,5-dimetoksy-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-(N-metyl-N-(pyridin-3-yl-metyl)-aminosulfonyl)-fenyl)-benzamid med smeltepunkt 213°C
197. ) 4,5-dimetoksy-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-(N-(pyirdin-3-yl-metyl)-aminosulfonyl)-fenyl)-benzamid med smeltepunkt 216°C
198. ) 5-klor-2-(2,4-dimetyl-tiazol-5-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 190°C
199. ) 4,5-dimetoksy-2-(4-klor-fenylsulfonylamino)-N-(4-(3,5-dimetyl-piperidin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 249°C (dek.)
200. ) 2-(4-klor-fenylsulfonylamino)-N-(4-(N-metyl-N-(pyridin-3-yl-metyl)-amino-sulfonyl)-fenyl)-benzamid; harpiks
201. ) 3,4-dimetoksy-2-(4-klor-fenylsulfonylamino)-N-(4-(N-metyl-N-(pyridin-3 -yl-metyl)-aminosulfonyl)-fenyl)-benzamid med smeltepunkt 241°C
202. ) 5-brom-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-3-metylfenyl)-benzamid med smeltepunkt 249°C
203. ) 5-brom-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 244°C
204. ) 5-brom-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 197°C
205. ) 4,5-dimetoksy-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(l,2,3,4-tetrahydroisokinolin-2-sulfonyl)-fenyl)-benzamid med smeltepunkt 213°C
206. ) 4,5-dimetoksy-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 232°C
207. ) 4,5-dimetoksy-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(cis-2,6-dimetyl-piperidin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 213°C
208. ) 5-klor-2-(3,5-dimetyl-isoksazoL
isokinolin-2-sulfonyl)-fenyl)-benzamid med smeltepunkt 260°C
209. ) 5-klor-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-(N-metyl-N-(pyirdin-3-yl-metyl)-aminosulfonyl)-fenyl)-benzamid med smeltepunkt 65°C (sintring)
210. ) 6-metyl-2-(4-klor-fenylsulfonylamino)-N-(4-(perhydroazepin-1 -sulfonyl)-fenyl)-benzamid med smeltepunkt 151°C
211. ) 6-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(pyrrolidin-1 -sulfonyl)-fenyl)-benzamid med smeltepunkt 217°C
213. ) 5-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(N-etyl-N-(pyridin-4-yl-metyl)-amino-sulfonyl)-fenyl)-benzamid; harpiks
214. ) 2-(4-klor-fenylsulfonylamino)-N-(4-tiomorfolin-4-sulfonyl)-fenyl)-benzamid med
smeltepunkt 209°C
215. ) 3-metyl-2-(4-klor-fenylsulfonylamino)-N-(4-(N-metyl-N-(2-(pyridin-2-yl)-etyl)-aminosulfonyl)-fenyl)-benzamid med smeltepunkt 193°C
216. ) 4,5-difluor-2-(4-klor-fenylsulfonylamino)-N-(4-(4-aminokarbonyl-piperidin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 227°C
217. ) 4,5 -difluor-2-(4-klor-fenylsulfonylamino)-N-(4-(4-(2-hydroksyetyl)-piperazin-1 -
sulfonyl)-fenyl)-benzamid; harpiks
218. ) 5-klor-4-metoksy-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid; olje
219. ) 5-klor-4-metoksy-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(cis-2,6-dimetylmorfolin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 89°C
221.) 4,5-dimetoksy-2-(4-klor-fenylsulfonylamino)-N-(4-cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-benzamid.natriumsalt med smeltepunkt 330°C (dek.)
222. ) 5-klor-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-(cis-2,6-dimetyl-morf^
4-sulfonyl)-fenyl)-benzamid med smeltepunkt 230°C
223. ) 5-klor-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-(3,5-dimetylpiperidin-l-sulfonyl)-fenyl)-benzamid med smeltepunkt 61°C
224. ) 5-klor-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 286°C
225. ) 5-klor-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-fenylsulfonyl)-fenyl)-benzamid
med smeltepunkt 227°C
226. ) 4-klor-2-(4-klor-fenylsulfonylamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-benzamid med smeltepunkt 103°C
Farmakologisk undersøkelse
1) Aktivering av den oppløselige guanylatcyklase
Aktiveringen av den oppløselige guanylatcyklase (sGC) som katalyserer omdanningen av guanosintrifosfat (GTP) til cyklisk guanosinmonofosfat (cGMP) og pyrofosfat, ved hjelp av forbindelsene ifølge oppfinnelsen, ble kvantifisert ved hjelp av en enzym-immunoanalyse (EIA) fra Amersham. For dette formål ble stoffene som skulle testes inkubert innledningsvis med sGC i mikrotiterplater og mengden dannet cGMP ble bestemt.
Den sGC som ble benyttet var isolert fra bovinlunge (se "Methods in Enzymology", vol. 195, side 137). Testoppløsningene (100 ul pr. brønn) inneholdt 50 mM trietanolamin (TEA) buffer (pH 7,5), 3 mM MgCl2, 3 mM redusert glutation (GSH), 0,1 mM GTP, 1 mM 3-isobutyl-l-metylxantin (IBMX), egnet fortynnet enzymoppløsning og substansen som skulle testes, eller, i kontrollforsøkene, oppløsningsmidlet. Stoffene som skulle testes ble oppløst i dimetylsulfoksyd (DMSO) og oppløsningen ble fortynnet med DMSO:vann slik at sluttkonsentrasjonen c for stoffet som skulle test i testoppløsningen hadde en verdi som angitt i tabellen. DMSO-konsentrasjonen i testoppløsningen var 5% volum/volum. Reaksjonen ble initiert ved tilsetning av sGC. Reaksjonsblandingen ble inkubert ved 37°C i 15-20 minutter og så stanset ved isavkjøling og tilsetning av stopp-reagensen (50 mM EDTA, pH 8,0). En aliquot på 50 ul ble tatt og benyttet for bestemmelse av cGMP-innholdet ved bruk av Amershams cGMP-EIA-kitt-acetyleringsproto-koll. Absorpsjonen av prøvene ble målt ved 450 nm med referansebølgelengde 620 nm) i en mikrotiterplateleser. cGMP-konsentrasjonen ble bestemt ved bruk av en standard-kurve som var oppnådd under de samme testbetingelser. Aktiveringen av sGC med en testsubstans er gitt den n-gangers stimulering av basal-enzymaktiviteten som ble funnet i kontrollforsøkene (ved bruk av oppløsningsmiddel i stedet for testsubstans) (beregnet ved bruk av formelen: n x stimulering = [cGMP]testsubstans/[cGMP]kontroii)-
Man oppnådde de følgende resultater:
2) Relaksering av rotteaorta
For dette formål ble normotensive Wistar-Kyoto-hannrotter avlivet ved et slag mot nakken. Abdominalkaviteten og toraks ble åpnet ved hjelp av en medium sternotomi. Den senkende aorta ble derefter fjernet, befridd for bindevev og delt i 8 ringer med en lengde på rundt 4 mm. Spissen av en pinsett ble innført i lumen av 4 av de 8 ringene. Endotelium ble fjernet ved forsiktig å rulle ringene over spissen av pinsetten. Alle 8 aortaringer (4 med endotelium og 4 uten endotelium) ble derefter suspendert i et organbad (Schuler-Organbad; Hugo Sachs Elektronik) ved en konstant temperatur på 37°C for isometrisk bestemmelse av den kontraktile tone. 130 minutter ble ringene kalibrert ved en hvilespenning på 1 g i karbonert (95% 02; 5% C02) Krebs-Henseleit-oppløsning (sammensetning: Na<+> 144,0 mM; K<+> 5,9 mM; Cl" 126,9 mM; Ca<2+> 1,6 mM; Mg<2+> 1,2 mM; H2P04" 1,2 mM; S04<2>' 1,2 mM; HC03" 25,0 mM; D-glucose 11,1 mM) ved pH 7,4.1 tillegg ble 1 umol/1 indometacin satt til Krebs-Henseleit-oppløsningen for å inhibere prostaglandinbiosyntese. Ringene ble derefter prekontraktert ved tilsetning av fenylefrin (konsentrasjon i oppløsningen: 1 uM) og den endotelium-avhengige relaksering eller det funksjonelle tap av endotelium ble testet ved tilsetning av acetylcholin (konsentrasjon i oppløsningen: 1 uM). Efter en 30-minutters vaskeperiode ble ringene så igjen prekontraktert ved tilsetning av fenylefrin (1 uM), og relakseringsvirkningene for testsubstansene med formel I ble bestemt ved administrering av kumulative doser av den sistnevnte. Data er bedømt ved standardmetoder. Gitt er konsentrasjonen IC50 ved hvilken kontraksjonen inhiberes med 50% (50% relaksasjon).
Man oppnådde de følgende resultater:
3) Hemodynamisk effekt i gris.
Tre griser (tysk landrase) ble anestetisert (Ketamine 20 mg/kg i.m., Metomidate 8 mg/kg i.p., Xylazine 2,5 mg/kg i.m. og Pentobarbital 25 mg/kg i.v. som en bolus pluss 0,16 mg/kg pr. minutt). Trakea ble intubert og dyrene kunstig gitt respirasjon med luft. Oksygen ble tilsatt for å holde blodgassparametrene innen det normale området. For å notere blodtrykket (BP; BP(s) = systoliske blodtrykk, BP(d) = diastoliske blodtrykk) ved hjelp av en Statham 23Db trykktransduser ble et kateter innført i den høyre A. Femoralis. Det venstre ventrikulærtrykk (LVP), det venstre ventrikulær-slutt-diastoliske trykk (LVEDP), kontraktiliteten (dP/dt) og pulsen (HR) ble bestemt med et Millar PC 350 kateter "tip manometer" som ble innført i den høyre ventrikkel. Etter en stabili-seringsperiode for de hemodynamiske parametere på 30 minutter, ble testsubstansen administrert i den antydede dose til den eksponerte duodenum ved hjelp av et kateter. De bestemte data ble bedømt i henhold til standardmetoder. Gitt er gjennomsnittet og standardavviket (M ± SEM) av utgangsverdiene og av de maksimale endringer av de individuelle parametere (= maksimale effekter).
De følgende resultater ble oppnådd:
Forbindelse fra eksempel 88 (dosering 10 mg/kg i.d.)
Claims (15)
1.
Forbindelse, karakterisert ved formel (I):
der
A<1> er fenylen som kan være usubstituert eller substituert med en eller flere identiske eller forskjellige substituenter fra serien halogen, CM-alkyl, CF3, -O-CM-alkyl og -CN;
ringen A<2> som omfatter de to karbonatomene som bærer gruppene R<2->S02-NH- og C(=X)-NH- er en benzenring, en pyridinring, en tiofenring eller en pyrazolring;
R<1> er Ci-7-alkyl eller er fenyl som kan være usubstituert eller substituert med en eller flere, like eller forskjellige substituenter fra serien halogen, CM-alkyl, fenyl, CF3, NO2, -O-CM-alkyl, Ci.2-alkylendioksy, NH2, -NH-CO-CM-alkyl, -CN, -CO-NH2, -CO-OH og -CO-O-CM-alkyl; eller hvis tallet n i gruppen R<1->S(0)n- er 2, kan R<1> også være NR<5>R<6>;
R<2> er aryl;
R<3> angir en eller flere, like eller forskjellige rester fra serien hydrogen, halogen, CF3, - O-CM-alkyl, -CN, og CM-alkyl;
R<5> og R<6> er uavhengig av hverandre hydrogen eller Ci.9-alkyl som kan være usubstituert eller substituert med aryl; eller C2.9-alkenyl, eller C3.9-cykloalkyl, eller CM-alkyl-0-Ci-3-alkyl; eller
R<5> og R<6> danner sammen med nitrogenatomet hvor til de er bundet en 5- til 7-leddet, mettet eller partielt umettet heterocyklyl som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde ett ytterligere ringheteroatomer fra serien N, 0 og S og som kan være substituert med en eller flere, like eller forskjellige substituenter fra serien Ci-3-alkyl, hydroksy-Ci-3-alkyl, aryl, karbamoyl, hydroksy og okso, og til hvilken en benzenring kan være kondensert;
aryl er fenyl eller heteroaryl som kan være substituert med en eller flere, like eller forskjellige substituenter fra serien halogen, CM-alkyl, fenyl, CF3, NO2, -O-CM-alkyl, Ci.2-alkylendioksy, NH2, -NH-CO-CM-alkyl, -CN, -CO-NH2, -CO-OH, og -CO-O-CM-alkyl;
heteroaryl er en rest av en monocyklisk, 5- eller 6-leddet aromatisk heterocykel som inneholder ett eller to like eller forskjellige heteroatomer fra serien N, 0 og S;
n er 0 eller 2;
XerO;
i alle sine stereoisomere former og blandinger derav i alle forhold, og deres fysiologisk akseptable salter; hvor kun opptil to nitrogrupper kan være tilstede i en forbindelse av formel (I).
2.
Forbindelse med formel (I) ifølge krav 1, karakterisert v e d at
A<1> er fenylen som er usubstituert eller substituert med en eller flere, like eller forskjellige substituenter valgt blant halogen, CM-alkyl, CF3, -O-CM-alkyl og -CN;
ringen A<2> som omfatter de to karbonatomer som bærer gruppene R<2->S02-NH og C(=X)-NH- er en benzenring;
R1 er NR5R6;
R<2> er aryl;
R<3> angir en eller flere, like eller forskjellige rester valgt blant hydrogen, halogen, CF3, -O-CM-alkyl, -CN og CM-alkyl;
R<5> og R<6> sammen med nitrogenatomet som bærer R<5> og R<6> danner en 5- til 6-leddet, mettet heterocykel som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde et ytterligere ringheteroatom, valgt blant N, 0 og S og som kan være substituert med en eller flere, like eller forskjellige rester valgt blant Ci-3-alkyl, hydroksy-Ci-3-alkyl-, aryl, karbamoyl, hydroksy og okso;
aryl er fenyl eller 5- eller 6-leddet heteroaryl inneholdende et eller flere, like eller forskjellige ringheteroatomer, valgt blant N, O og S, hvilke rester alle kan være substituert med en eller flere, like eller forskjellige substituenter fra serien halogen, CM-alkyl, CF3, N02, -O-CM-alkyl, -NH-CO-CM-alkyl og-CN;
ner 2;
X er oksygen;
i alle sine stereoisomere former og blandinger derav i alle forhold, og deres fysiologisk akseptable salter.
3.
Forbindelse med formel (I) ifølge krav 1 og/eller 2, karakterisert ved at
A<1> er en usubstituert, toverdig fenylenrest;
ringen A<2> som omfatter de to karbonatomer som bærer gruppene R<2->S02-NH og C(=X)-NH- er en benzenring;
R1 er NR5R6;
R er aryl;
R<3> angir en eller flere, like eller forskjellige rester valgt blant hydrogen, halogen, -O-CM-alkyl og CM-alkyl;
R<5> og R<6> sammen med nitrogenatomet som bærer R<5> og R<6> danner en mettet 6-leddet heterocykel som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde et ytterligere ringheteroatom valgt blant N, O og S og som kan være substituert med en eller flere, like eller forskjellige rester valgt blant Ci-3-alkyl, aryl, okso og karbamoyl;
aryl er fenyl eller 5- eller 6-leddet heteroaryl inneholdende en eller flere, like eller forskjellige ringheteroatomer valgt blant N, O og S, hvilke rester alle kan være substituert med en eller flere, like eller forskjellige substituenter, valgt blant halogen, CM-alkyl, CF3 og -O-CM-alkyl;
n er 2;
X er oksygen;
i alle dens stereoisomere former og blandinger derav i alle forhold og dens fysiologisk akseptable salter.
4.
Forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 3, karakterisert ved at
A<1> er en usubstituert, toverdig 1,4-fenylenrest;
ringen A<2> som omfatter de to karbonatomer som bærer gruppene R<2->S02-NH og C(=X)-NH- sammen med restene R<3> er en benzenring som bærer en eller to substituenter valgt blant serien klor og metoksy;
R1 er NR5R6;
R<2> er fenyl eller tienyl, hvilke rester alle er substituert med et eller to kloratomer;
R<5> og R<6> sammen med nitrogenatomet som bærer R<5> og R<6> danner en mettet 6-leddet heterocykel som i tillegg til nitrogenatomet som bærer gruppene R<5> og R<6> kan inneholde et ytterligere ringheteroatom valgt blant 0 og S, og som er usubstituert eller substituert med en eller to metylrester;
n er 2;
X er oksygen;
i alle dens stereoisomere former og blandinger derav i alle forhold og dens fysiologisk akseptable salter.
5.
Forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 4, karakterisert ved at den er 2-(4-klor-fenylsulfonylamino)-4,5-dimetoksy-N-(4-(tiomorfolin-4-sulfonyl)-fenyl)-benzamid og dens fysiologisk akseptable salter.
6.
Forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 4, karakterisert ved at den er 2-(4-klor-fenylsulfonylamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-4,5-dimetoksy-benzamid og dens fysiologisk akseptable salter.
7.
Forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 4, karakterisert ved at den er 5-klor-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid og dens fysiologisk akseptable salter.
8.
Forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 3, karakterisert ved at 5-klor-2-(3,5-dimetyl-isoksazol-4-sulfonylamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-benzamid og den fysiologisk akseptable salter.
9.
Et salt av en forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 8, karakterisert ved at det er et natrium salt.
10.
Forbindelse ifølge ett eller flere av kravene 1 til 4, 6 og 9, karakterisert ved at den er 4,5-dimetoksy-2-(4-klor-fenylsulfonylamino)-N-(4-(cis-2,6-dimetyl-morfolin-4-sulfonyl)-fenyl)-benzamid natriumsalt.
11.
Forbindelse ifølge ett eller flere av kravene 1 til 4, 7 og 9 karakterisert ved at den er 5-klor-2-(5-klor-tiofen-2-sulfonylamino)-N-(4-(morfolin-4-sulfonyl)-fenyl)-benzamid natriumsalt.
12.
Fremgangsmåte for fremstilling av en forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 11, karakterisert ved at den omfatter omdanning av en cyklisk aminokarboksylsyre med formel (II) til en sulfonylaminokarboksylsyre med formel (III) og omdanning av forbindelsen med formel (III) til en forbindelse med formel (I),
eller omdanning av en cyklisk nitrokarboksylsyre med formel (IX) til et nitrokarboks-amid med formel (XII) og omdanning av forbindelsen med formel (XII) til en forbindelse med formel (I) ved reduksjon av nitrogruppen til en aminogruppe og sulfonylering av aminogruppen,
der i formlene (I), (II), (III), (IX) og (XII), gruppene A<1>, A2, R1, R2, R3 og X og n har den betydning som er angitt i kravene 1 til 11, idet rester eller funksjonelle grupper kan være til stede i beskyttet form eller i form av forløpergrupper.
13.
Forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 11 og/eller dens fysiologisk akseptable salter for bruk som farmasøytikum.
14.
Farmasøytisk preparat, karakterisert ved at det omfatter en eller flere forbindelser med formel (I) som angitt i ett eller flere av kravene 1 til 11 og/eller deres fysiologisk akseptable salter og en farmasøytisk akseptabel bærer.
15.
Anvendelse av en forbindelse med formel (I) ifølge ett eller flere av kravene 1 til 11 og/eller fysiologisk akseptable salter derav for fremstilling av et preparat for bruk ved terapi eller profylakse av kardiovaskulære sykdommer, endotelial dysfunksjon, diastolisk dysfunksjon, aterosklerose, hypertensjon, angina pectoris, tromboser, restenoser, myokardialinfarkt, slag, kardial insufflsiens, pulmonær hypertoni, erectil dysfunksjon, astma bronkiale, kronisk nyreinsuffisiens, diabetes eller cirrhose på leveren, eller for å forbedre begrenset hukommelsesytelse eller evnen til læring.
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DE19830430A DE19830430A1 (de) | 1998-07-08 | 1998-07-08 | Schwefelsubstituierte Sulfonylamino-carbonsäure-N-arylamide, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
DE19903126A DE19903126A1 (de) | 1999-01-27 | 1999-01-27 | Schwefelsubstituierte Sulfonylamino-carbonsäure-N-arylamide, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
PCT/EP1999/004426 WO2000002851A1 (en) | 1998-07-08 | 1999-06-25 | Sulfur substituted sulfonylaminocarboxylic acid n-arylamides, their preparation, their use and pharmaceutical preparations comprising them |
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DK1095016T3 (da) | 1998-07-08 | 2006-03-13 | Sanofi Aventis Deutschland | Svovlsubstituerede sulfonylaminocarboxylsyre-N-arylamider, deres fremstilling, deres anvendelse og farmaceutiske præparater omfattende dem |
DE19830431A1 (de) * | 1998-07-08 | 2000-01-13 | Hoechst Marion Roussel De Gmbh | Sulfonylamino-carbonsäure-N-arylamide als Guanylatcyclase-Aktivatoren |
GB9824579D0 (en) * | 1998-11-10 | 1999-01-06 | Novartis Ag | Organic compounds |
DE19944226A1 (de) | 1999-09-15 | 2001-03-29 | Aventis Pharma Gmbh | Verfahren zum Nachweis von oxidierten Formen der löslichen Guanylatzyklase und Verfahren zum Screening nach Aktivatoren der löslichen Guanylatzyklase mit oxidiertem Hämeisen |
DE60044382D1 (de) * | 1999-11-26 | 2010-06-17 | Shionogi & Co | NPYY5-Antagonisten |
SE0001899D0 (sv) | 2000-05-22 | 2000-05-22 | Pharmacia & Upjohn Ab | New compounds |
GB2365426A (en) * | 2000-08-01 | 2002-02-20 | Pantherix Ltd | Bactericidal benzamide derivatives |
AU2001288518A1 (en) * | 2000-08-30 | 2002-03-13 | Primecyte, Inc. | Methods for treating tumors using sulfonyl compounds |
EP1193267A1 (en) * | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active hydrophilic sulfonamide derivatives as inhibitors of protein JunKinases |
EP1193256A1 (en) * | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active benzsulfonamide derivatives as inhibitors of JNK proteins |
EP1193268A1 (en) * | 2000-09-27 | 2002-04-03 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases |
AU2002213048A1 (en) * | 2000-10-05 | 2002-04-15 | Smith Kline Beecham Corporation | Phosphate transport inhibitors |
US7102009B2 (en) | 2001-01-12 | 2006-09-05 | Amgen Inc. | Substituted amine derivatives and methods of use |
US7105682B2 (en) | 2001-01-12 | 2006-09-12 | Amgen Inc. | Substituted amine derivatives and methods of use |
US6878714B2 (en) | 2001-01-12 | 2005-04-12 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
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- 2007-12-18 US US12/000,844 patent/US8106213B2/en not_active Expired - Fee Related
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2012
- 2012-01-06 US US13/345,223 patent/US8541410B2/en not_active Expired - Fee Related
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