SE458606B - 2-PHTALIMIDOETAN SULPHON-N-ARYLAMIDES AND PROCEDURES FOR PREPARING THESE - Google Patents

2-PHTALIMIDOETAN SULPHON-N-ARYLAMIDES AND PROCEDURES FOR PREPARING THESE

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SE458606B
SE458606B SE8701524A SE8701524A SE458606B SE 458606 B SE458606 B SE 458606B SE 8701524 A SE8701524 A SE 8701524A SE 8701524 A SE8701524 A SE 8701524A SE 458606 B SE458606 B SE 458606B
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formula
group
same
hydrogen
refer
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SE8701524D0 (en
SE8701524L (en
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L Andersen
M Kangasaho
H Nikander
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Huhtamaeki Oy
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Priority to SE8701524A priority Critical patent/SE458606B/en
Publication of SE8701524D0 publication Critical patent/SE8701524D0/en
Priority to PCT/FI1988/000043 priority patent/WO1988007991A1/en
Priority to AU14994/88A priority patent/AU1499488A/en
Priority to JP63502909A priority patent/JPH02502996A/en
Priority to EP88902862A priority patent/EP0355098A1/en
Publication of SE8701524L publication Critical patent/SE8701524L/en
Publication of SE458606B publication Critical patent/SE458606B/en
Priority to FI894315A priority patent/FI894315A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

3' 458 606 f b) 'där Z = 0, N eller S. 3 '458 606 f b)' where Z = 0, N or S.

Uppfinníngen avser också ett förfarande för framställning av dessa nya föreningar. Kännetecknat för förfarandet är, att 1) en ftalimidoetansulfonylklorid med formeln II CO NH-CH2CH2SO2Cl CO omsätts med en amin med formeln III fl NH-(CH2)n-R2 där n, R1 och R2 avser det samma som ovan, 2) en ftalimidoetansulfonamid med formel IV CO R1 \\\NH CH CH SO šfi co /, 2 2 2 där R1 avser det samma som ovan, alkyleras med ett alkyleríngsmedel innehållande gruppen R2 avser det samma som ovan, (II) (III) (Iv) lämpligt -(CH2)n-R2, där n och 4. 5 8 .6 0.6. I 3) en ftalimidoetansulfonamid med formeln V CO\\\ É NH-cugcnzsoz-N- (C112 ),,-R2 (V) CO där n och R2 avser det sama som ovan, alkyleras med lämpligt alkyleringsmedel innehållande gruppen R1, som definierats ovan, 4) en ftalímid med formeln VI CO NH (VI) CO'// eller dess salt omsätts med en förening med formeln VII RI s , x-cfizcnzsozu- (eng )n-R2 (VII) där n, R1 och R2 avser det sama som ovan och X är en utbytbar grupp, såsom t.ex. halogen, eller 5) en ftalsyraanhydrid med formeln VIII \ G o (VIII) / . eller motsvarande syra omsätts med en amid med formeln IX :21 HZN-CHZCHZSOZN- ( CH2 )n-R2 (IX) där n, R1 och R2 avser det samma som ovan. ._'4ss eos 00 ' " \ _ cgua-cnacuzsoznnz 14123911-112 ø . V . ca Û \“H=H=°H2Ss>2-3-<=H2>..-R= _ ca co \ cnx *31 /HH-Cfiacflgsflïgfll _ ' _ nH-cxzcxzsoz-na °° co, CG R1 _ \ 's I /zzx-cflzcnz oz-N-(c n-nz co _ '31 / @ x-cxåcxzsozlz -(cH¿)n-n¿ :H ef) nzu-cxzcxzsozn -uzxgn-Rz co\ @ \ coon nu co ¶ f (CI co \ o Qi , co 458 606 I den finska patentskriften FI 67214 beskrivs vissa taurinalkyl- amidderivat och deras antiepileptiska egenskaper. Nu har man överraskande funnit att motsvarande arylderivat besitter anti- arytmiska egenskaper.The invention also relates to a process for the preparation of these novel compounds. Characteristic of the process is that 1) a phthalimidoethanesulfonyl chloride of the formula II CO NH-CH 2 CH 2 SO 2 Cl CO is reacted with an amine of the formula III f1 NH- (CH2) n-R2 where n, R1 and R2 refer to the same as above, 2) a phthalimidoethanesulfonamide with formula IV CO R 1 \\\ NH CH CH SO š fi co /, 2 2 2 where R 1 refers to the same as above, is alkylated with an alkylating agent containing the group R 2 refers to the same as above, (II) (III) (Iv) suitably - (CH2) n-R2, where n and 4. 5 8 .6 0.6. In 3) a phthalimidoethanesulfonamide of the formula V CO 2 \ NH 4 NH-cugnzsoz-N- (C 11)), - R 2 (V) CO where n and R 2 refer to the same as above, are alkylated with a suitable alkylating agent containing the group R above, 4) a phthalimide of the formula VI CO NH (VI) CO '// or its salt is reacted with a compound of the formula VII RI s, x-c fi zcnzsozu- (eng) n-R2 (VII) where n, R1 and R2 refers to the same as above and X is a substitutable group, such as e.g. halogen, or 5) a phthalic anhydride of the formula VIII \ G o (VIII) /. or the corresponding acid is reacted with an amide of formula IX: 21 HZN-CH 2 CH 2 SO 2 N- (CH 2) n -R 2 (IX) where n, R 1 and R 2 refer to the same as above. ._ '4ss eos 00' "\ _ cgua-cnacuzsoznnz 14123911-112 ø. V. Ca Û \“ H = H = ° H2Ss> 2-3 - <= H2> ..- R = _ ca co \ cnx * 31 / HH-C fi ac fl gs fl ïg fl l _ '_ nH-cxzcxzsoz-na °° co, CG R1 _ \'s I / zzx-c fl zcnz oz-N- (c n-nz co _ '31 / @ x-cxåcxzsozlz - (cH¿ ) nn¿: H ef) nzu-cxzcxzsozn -uzxgn-Rz co \ @ \ coon nu co ¶ f (CI co \ o Qi, co 458 606 Finnish patent specification FI 67214 describes certain taurine alkylamide derivatives and their antiepileptic properties. it has surprisingly been found that corresponding aryl derivatives possess antiarrhythmic properties.

Föreningarnas antiarytmiska effekt undersöktes in vitro på en rättas spontant pulserande förkamarpreparat under rytmstörningar förorsakade av akonitin (Holland WC & Burn JH, Br Med. J, vol. 1, 1031, 1958) samt in situ med hjälp av förhöjningen av fibrillationströskeln elektriskt inducerad i ett katthjärta (Szekeres L & Papp J, Handbook of Experimental Pharmacology, vol. XVI/3, 131, 1975). I tabellen l visas effekten av de sju effektivaste föreningarna i in vitro test jämförde med kinidin och lidokain. I in vitro testen var 20 föreningar effektivare än kinidin. I in situ testen var en del föreningar effektivare än kinidin och lidokain. 2-Ftalimidoetansulfon-N-[2-(3-dimety1- aminfenyl)ety1]amid hade en effekt, som tilltog betydligt, da dosen i in situ testen höjdes till 6 mg/kg i.v. Med denna dos var effekten på förkammaren +183 i 10% (p ( 0,01) och på kammaren + 68 i 9% (p { 0,01), för kinidin var motsvarande dos + 53 t 5% (p { 0,01) och + 36 å 6% (p { 0,01) samt för lidokain med en dos på 10 mg/kg i.v. + 90 i 17% (p { 0,01) och + 49 i 14% (p ( 0,05).The antiarrhythmic effect of the compounds was examined in vitro on a rectally spontaneous pulsating anterior chamber preparation during arrhythmias caused by aconitine (Holland WC & Burn JH, Br Med. J, vol. 1, 1031, 1958) and in situ using the elevation of the fibrillation threshold electrically induced in a cat heart (Szekeres L & Papp J, Handbook of Experimental Pharmacology, vol. XVI / 3, 131, 1975). Table 1 shows the effect of the seven most effective compounds in in vitro tests compared to quinidine and lidocaine. In the in vitro test, 20 compounds were more effective than quinidine. In the in situ test, some compounds were more effective than quinidine and lidocaine. 2-Phthalimidoethanesulfon-N- [2- (3-dimethylaminophenyl) ethyl] amide had an effect which increased significantly as the dose in the in situ test was increased to 6 mg / kg i.v. With this dose, the effect on the atrium was +183 in 10% (p (0.01) and on the chamber + 68 in 9% (p {0.01), for quinidine the corresponding dose was + 53 t 5% (p {0, 01) and + 36 å 6% (p {0.01) and for lidocaine with a dose of 10 mg / kg iv + 90 in 17% (p {0.01) and + 49 in 14% (p (0, 05).

Endast kinidin och 2-fta1imidoetansulfon-N-(3-dimety1amino- bensyl)amid var statistiskt pâtagbart verksamma som höjare av fibrillationströskeln i en elektriskt stimulerad kammare av en katt.Only quinidine and 2-phthalimidoethanesulfon-N- (3-dimethylaminobenzyl) amide were statistically significant as enhancers of the fibrillation threshold in an electrically stimulated chamber of a cat.

Tabell 1 Exempelföreningarnas verkan på med akonitin förorsakade rytm- störningar i ett spontant pulserande förkammarpreparat av ett râtthjärta samt förmågan att höja el-stimulationens fibrillations- tröskel in situ i förkammaren och kammaren till ett katthjärta. fi'4ss eos 6 Tabell 1 Akonitinarytmi in vitro Förändringen av fibril- tillför- latíonströskeln från lítlig- kontrollvärdet in situ hetsint- vid en dos av 4 mg/kg EC50 ervall ï.v.Table 1 The effect of the example compounds on aconitine-induced arrhythmias in a spontaneously pulsating atrial fibrillation preparation of a rat heart and the ability to raise the fibrillation threshold of electrical stimulation in situ in the atrium and ventricle of a cat heart. fi'4ss eos 6 Table 1 In vitro aconitrhythmia The change in the fibril supply threshold from the small control value in situ sin- at a dose of 4 mg / kg EC50 erval ï.v.

Förening N (pM) (95%) N förkam. kammare 2-fta1imidoetan- sulfon-N- 3-(4-klorfenyl)- propylamid (337) 8 0,6 (0,4-0,8) - - - 3-(fenyl)propyl- amíd (334) 8 1,4 (0,9-2,1) - - - (2,4-díklor- _ bensyl)amiå (325) 6 1,7 (0,9-3,1) _ 5 +l7il5% +4il3% (3,4-diklor- benSyl)amiâ (324) 6 1,9 (0,8-4,5) 5 +72il9% +25il3% (4-klorbensyl)- amiä (304) 6 2,2 (1,1-4,2) 5 +57il7% +l0i 8% (3-dímetylamin- 1 bensyl)amíd (320) 6 2,2 (0,5-9,3) 5 +30i 7% +38t1l% (3-trifluorometyl- 7 bensyl)amíd (327) 6 2,4 (0,9-6,4) 5 +26il5% +20i16% bensylamia (13o)l) 6 3,8 (2,s-e,s) - - - isopropylamiafl a 25,7 (19,a-33,s) s +42: 6% usfloæ Kínidin 8 20,3 (13,7-30,3) 20 +36å 6% _ +25á 8% Lídokain 6 234 (182~3l4) 8 +27il6% +25Éll% 1) Chemical Abstracts, Vol. 41 (1947) 6527 - 6529 2) FI-patent 67214 . . _ 458 606 Föreningarnas inverkan på hjärtats sammandragning och frekvens undersöktes med ett spontant pulserande förkammarpreparat av en råtta. Sprague-Dawleyhcnråttor (180 - 200 g) dekapitiserades och ur djurens hjärta preparerades förkammaren i oxiderad Tyrode- lösning (+30°C). Förkammaren fästes vid en isometrisk givare och fick stabilisera sig i 15 minuter med en 0,5 g tyngd i en med karbogen (02 95% + C02 5%) oxiderad Tyrode-lösning (+30°C).Compound N (pM) (95%) N comb. chamber 2-phthalimidoethanesulfon-N-3- (4-chlorophenyl) -propylamide (337) 8 0.6 (0.4-0.8) - - - (phenyl) propylamide (334) 8 1 , 4 (0.9-2.1) - - - (2,4-dichloro-benzyl) amino (325) 6 1.7 (0.9-3.1) _ 5 + 17755% + 4il3% ( 3,4-dichlorobenzyl) amia (324) 6 1.9 (0.8-4.5) 5 + 72il9% + 25il3% (4-chlorobenzyl) amia (304) 6 2.2 (1.1 -4.2) 5 + 57il7% + 10i 8% (3-dimethylamine-1-benzyl) amide (320) 6 2.2 (0.5-9.3) 5 + 30i 7% + 38t11% (3-trifluoromethyl - 7 benzyl) amide (327) 6 2,4 (0,9-6,4) 5 + 26il5% + 20i16% benzylamia (13o) l) 6 3,8 (2, se, s) - - - isopropylamia fl a 25.7 (19, a-33, s) s +42: 6% us fl oæ Kínidin 8 20.3 (13.7-30.3) 20 + 36å 6% _ + 25á 8% Lidokain 6 234 (182 ~ 3l4 ) 8 + 27il6% + 25Éll% 1) Chemical Abstracts, Vol. 41 (1947) 6527 - 6529 2) FI patent 67214. . 458 606 The effect of the compounds on the contraction and frequency of the heart was examined with a spontaneously pulsating atrial preparation of a rat. Sprague-Dawleyhn rats (180 - 200 g) were decapitated and from the animals' hearts the antechamber was prepared in oxidized Tyrode solution (+ 30 ° C). The atrium was attached to an isometric sensor and allowed to stabilize for 15 minutes with a weight of 0.5 g in a carbogen (O 2 95% + CO 2 5%) oxidized Tyrode solution (+ 30 ° C).

Efter'tillsättning av föreningen, som skall undersökas, registre- rades samandragningskraften och -frekvensen under 13 minuter.After addition of the compound to be tested, the contractile force and frequency were recorded for 13 minutes.

I tabell 2 anges verkan av nägra effektiva samandragningskraften ökande föreningar jämfört med g-strofantin. Sammandragnings- kraften ökande verkan visade sig speciellt dimetylaminbensyl- derivaten besitta. Vid de effektivaste doserna kunde också en sänkning av samandragningsfrekvensen iakttas. Det är också känt, att i en rättas spontant pulserande förkammarçreparat påverkar dessa parametrar varandra.Table 2 shows the effect of some effective contractile increasing compounds compared to g-strofantine. The increasing effect of the contraction force was found to possess the dimethylamine benzyl derivatives in particular. At the most effective doses, a decrease in the rate of contraction could also be observed. It is also known that in the spontaneously pulsating atrial fibrillation of a rectifier, these parameters affect each other.

Tabell 2 Några föreningars verkan på en rättas spontant pulserande förkammarpreparats sammandragningskraft och -frekvens in vitro (10 minuter efter testföreningens intagning). Resultatet anges som procent av värdena före aktivmedlets administrering (1 SE) .l' 458 606 . 1 8.Table 2 Effects of some compounds on the spontaneous pulsating antifreeze of a remedy in vitro (10 minutes after ingestion of the test compound). The result is given as a percentage of the values before the administration of the active agent (1 SE) .l '458 606. 1 8.

Tabell 2 Saman- Koncen- drg.kraft Frekvens tration i % av i % av Förening N pM kontroll kontroll 2-ftalimidoetansulfon-N- (3-dimetylaminbensyl)amid 8 10 150il6 91i3 (320) - 8 40 177116 78i3 2-(4-dimetylaminfenyl)etyl- 8 10 147i 9 82t3 amid (339) 4 40 2l3i38 71i5 3-(4-dimetylamínfenyl)propyl- 6 .10 911 9 84å3 amid (341) 6 40 131: s ssæs 3-(fenyl)propy1amid (334) ' 3 10 l2li12 87i3 3-(4-klorfenyl)propylamid (337) 4 10 92112 87t3 isopropylamia l) 4 10 89:14 esta g-strofantin. 6 10 127i 7 90i3 Lösningskontroll (DMSO) 8 - 85i 8 9414 1) FI 67214 Föreningarnas verkan på en anestetiserad hunds hjärtas samman- dragningskraft och -frekvens in vivo undersöktes med 2-ftal- imidoetansulfon- ( 3-dimetylamínbensyl ) amid , mexiletin användes som jämförelse.Table 2 Concentration concentration Frequency tration in% of in% of Compound N pM control control 2-phthalimidoethanesulfon-N- (3-dimethylaminebenzyl) amide 8 10 150il6 91i3 (320) - 8 40 177116 78i3 2- (4 -dimethylaminephenyl) ethyl- 8 10 147i 9 82t3 amide (339) 4 40 2l3i38 71i5 3- (4-dimethylaminophenyl) propyl- 6.10 911 9 84å3 amide (341) 6 40 131: ssæs 3- (phenyl) propylamide ( 334) '3 10 l2li12 87i3 3- (4-chlorophenyl) propylamide (337) 4 10 92112 87t3 isopropylamia l) 4 10 89:14 esta g-strofantin. 6 10 127i 7 90i3 Solution control (DMSO) 8 - 85i 8 9414 1) FI 67214 The effect of the compounds on the contractile force and frequency of an anesthetized dog's heart in vivo was investigated with 2-phthalimidoethanesulphone (3-dimethylaminebenzyl) amide, mexiletine used for comparison.

Hundar (10-20 kg) av båda könen nedsövdes med Nembutal 4581 606 (35mg/kg i.v.). Försöksdjuren andades spontant och bröstkorgen öppnades inte. Trycket i vänstra kammaren mättes med en kateter, som fördes in i hjärtat genom karotisartären. Tryckets maximala ökníngstakt (dP/dtmax) i den vänstra kammaren användes som mått på hjärtats sammandragningskraft. Det systemiska blodtrycket mättes med en tryckgivare från femoralartären.Dogs (10-20 kg) of both sexes were anesthetized with Nembutal 4581 606 (35 mg / kg i.v.). The experimental animals breathed spontaneously and the chest was not opened. The pressure in the left ventricle was measured with a catheter, which was inserted into the heart through the carotid artery. The maximum rate of increase of pressure (dP / dtmax) in the left ventricle was used as a measure of the contractile force of the heart. Systemic blood pressure was measured with a pressure sensor from the femoral artery.

Testföreningen (0,5-6 mg/kg i.v.) förorsakade en betydande ökning av sammandragningskraften dock utan att påverka hjärt- frekvensen. Genast efter ínjiceringen av testföreningen kunde en kraftig sänkning av blodtrycket noteras, som var så kortvarig, att den inte reflektoriskt kan förklara ökningen av hjärtats sammandragningskraft. Jämförelseföreningen mexile- tin förorsakade med sama koncentrationer statistiskt betydande sänkningar av hjärtats sammandragningskraft, frekvens och blodtryck (tabell 3).The test compound (0.5-6 mg / kg i.v.) caused a significant increase in the contractile force, however, without affecting the heart rate. Immediately after the injection of the test compound, a sharp drop in blood pressure could be noted, which was so short-lived that it could not reflexively explain the increase in the contractile force of the heart. With the same concentrations, the comparison association mexilatin caused statistically significant reductions in the contractile force, frequency and blood pressure of the heart (Table 3).

Tabell 3 2-Ftalimidoetansulfon-N-(3-dimetylamínbensyl)amidens (320) och mexiletinets(MEX) verkan på hjärtats sammandragninskraft (dP/dtmax), frekvens och systemiska blodtryck hos anesteti- serade hundar. Tabellen visar de procentuella förändringarna jämfört med läget före aktivmedlets injicering (i SE, N = 5) ON mflmmn wa wH«~m+ mä m«HH| mfl @«oH+ mä HH«m«| H ««m~« w vd ßflßfln nfl oH«on+ ß ¶m«m| NH w«o~+ m m«~H| H m««H| w m @«>| Nfl >«-+ w. @«H| OH @«m+ ß m«m| H ««ß| N m .äE. 3, EE; Awv ÉÉs.3 .3s..w. Éë: S. Éëc .wv .ïfi wfiu zu: uflp omm ufiu was øflø oflm ufiv xw: øfl» ofln mx\ma vunna. . muwcmëämw .mcflšonm xuænuwoflm ¶ mon m anamma '4ss sne 4-53 ÖÛG 11 Det har också visat sig, att de uppfinningsenliga föreningarna rätt kraftigt och långvarigt sänker blodtrycket hos anesteti- serade katter. Katter (2,5 - 3,5 kg) av båda könen anestetí- serades med kloralosuretan (50 + 300 mg/kg i.v.). Blodtrycket mättes i femoralartären med en tryckgivare. Resultatena anges i tabell 4.Table 3 2-Phthalimidoethanesulfon-N- (3-dimethylaminobenzyl) amide (320) and mexiletine (MEX) effect on cardiac contractility (dP / dtmax), frequency and systemic blood pressure in anesthetized dogs. The table shows the percentage changes compared to the situation before the injection of the active substance (in SE, N = 5) ON m fl mmn wa wH «~ m + mä m« HH | m fl @ «oH + mä HH« m «| H «« m ~ «w vd ß fl ß fl n n fl oH« on + ß ¶m «m | NH w «o ~ + m m« ~ H | H m «« H | w m @ «> | N fl> «- + w. @« H | OH @ «m + ß m« m | H «« ß | N m .äE. 3, EE; Awv ÉÉs.3 .3s..w. Éë: S. Éëc .wv .ï fi w fi u zu: u fl p omm u fi u was ø fl ø o fl m u fi v xw: ø fl »o fl n mx \ ma vunna. . muwcmëämw .mc fl šonm xuænuwo fl m ¶ mon m anamma '4ss sne 4-53 ÖÛG 11 It has also been shown that the inventive compounds lower the blood pressure of anesthetized cats quite sharply and for a long time. Cats (2.5 - 3.5 kg) of both sexes were anesthetized with chloralosurethane (50 + 300 mg / kg i.v.). Blood pressure was measured in the femoral artery with a pressure sensor. The results are given in Table 4.

Tabell 4 Några föreningars inverkan på medelblodtrycket hos anestetiserade katter. Resultaten anges som procenter av motsvarande värden före test- föreningens intagande (i SE, N = 5) Dos _(mg/kg) Förändning av Tid Förening i.v. blodtrycket (%) (min) 2-Ftalimidoetansulfon-N- (4-klorbensyl)amíd (304) 2 -33i4 7 -52i6 17 (3-dimetylaminbensyl)- 2 -4013 4 amid (320) 4 -42æ3 6 (3,4-díklorbensyl)- 2 -49t4 6 amid (324) 4 -56i6 13 (2,4-dik1orbensyl)- 2 -30f5 4 amiâ (325) 4 -56i3 16 (3-trifluormetyl- 2 -34i5 5 bensyl)amíd (327) 4 -4315 7 isopropylamid 1) 2 -22i3 4 4 -44-.1-5 1) FI-patent nr 67214 ,' 458 eos 12i Föreningarna enligt uppfinningen kan framställas enligt följande exempel. I 7 Exemgel 1 2-Ftalimidoetansulfon-N-(4-metoxibensyl)-amid Till en blandning av 30 ml metylenklorid och 6 ml 6 M kalium- karbonatvattenlösning sattes vid 0 - S°C 0,01 mol 4-metoxi- bensylamin. Ftalimidoetansulfonylklorid (0,0l mol) tillsattes under 5 minuter. Blandningen omrördes i 30 minuter, varefter 25 ml vatten tillsattes. Skiktena separerades, den organiska fasen tvättades med vatten, torkades och lösningsmedlet destil- lerades bort. Produkten kristalliserades ur vattenhaltig etanol.Table 4 Effects of some compounds on mean blood pressure in anesthetized cats. The results are given as percentages of the corresponding values before taking the test compound (in SE, N = 5) Dose _ (mg / kg) Change in Time Compound i.v. blood pressure (%) (min) 2-Phthalimidoethanesulfon-N- (4-chlorobenzyl) amide (304) 2 -33i4 7 -52i6 17 (3-dimethylaminebenzyl) -2-4013 4 amide (320) 4 -42e3 6 (3, 4-dichlorobenzyl) -2-49,4-amide (324) 4 -56i6 13 (2,4-dichlorobenzyl) -2-30f5 4 amiâ (325) 4 -56i3 16 (3-trifluoromethyl-2-34i5benzyl) amide (324) 327) 4 -4315 7 isopropylamide 1) 2 -22i3 4 4 -44-.1-5 1) FI Patent No. 67214, '458 eos 12i The compounds of the invention can be prepared according to the following examples. I 7 Example 1 2-Phthalimidoethanesulfon-N- (4-methoxybenzyl) -amide To a mixture of 30 ml of methylene chloride and 6 ml of 6 M potassium carbonate aqueous solution was added at 0 - S ° C 0.01 mol of 4-methoxybenzylamine. Phthalimidoethanesulfonyl chloride (0.01 mol) was added over 5 minutes. The mixture was stirred for 30 minutes, after which 25 ml of water were added. The layers were separated, the organic phase was washed with water, dried and the solvent was distilled off. The product was crystallized from aqueous ethanol.

Utbytet: 2,9 g (78 %: teor. 3,7 g) sp.= 122 - 124°d Exemgel 2 2-Ftalimidoetansulfon-N-(4-metylbensyl)-amid Denna förening framställdes enligt exempel l ur 4-metylbensyl- amin. Utbytet var 1,9 g (53%; teor. 3,6 g). sp.= 15o - 1s1°c Exempel 3 2-Ftalimidoetansulfon-N-(4-nitrobensyl)amid Föreningen framställdes enligt exempel 1 ur 4-nitrobensylamin.Yield: 2.9 g (78%: theory, 3.7 g) mp = 122 DEG-124 DEG C. Example 2 2-Phthalimidoethanesulfon-N- (4-methylbenzyl) -amide This compound was prepared according to Example 1 from 4-methylbenzyl - amin. The yield was 1.9 g (53%; theory, 3.6 g). mp = 15 DEG-15 DEG C. Example 3 2-Phthalimidoethanesulfone-N- (4-nitrobenzyl) amide The compound was prepared according to Example 1 from 4-nitrobenzylamine.

Utbytet var 2,7 g (69 %; teor. 3,9 g).The yield was 2.7 g (69%; theory, 3.9 g).

Sp.: 197 - l99°C . . (458 606 13 Exemgel 4 2-Ftalimídoetansulfon-N-metyl-N-bensylamid Föreningen framstä1ldes'enlígt exemplet 1 ur N-metylbensylamin.Mp: 197-199 ° C. . Example 4 2-Phthalimidoethanesulfone-N-methyl-N-benzylamide The compound was prepared according to Example 1 from N-methylbenzylamine.

Utbytet var 2,6 g (72 %, teor. 3,6 g) Sp.: 160 - 162°c Exemgel 5 2-Ftalimidoetansulfon-N-furfurylamid Föreningen framställdes enligt exempel l ur furfurylamin.The yield was 2.6 g (72%, theory, 3.6 g) Mp: 160 DEG-162 DEG C. Example 2 2-Phthalimidoethanesulfone-N-furfurylamide The compound was prepared according to Example 1 from furfurylamine.

Utbytet var 2,7 g (81 %; teor. 3,34 g) sp.= 134 - 136°c Exemgel G 2~Ftalimídoetansulfon-N-(4-karbometoxibensy1)amid Föreningen framställdes enligt exemplet 1 ur metyl-4-amino- metylhensoat. Utbytet 3,0 g (75 %; teor. 4,02 g) Sp.: 172 - l74°C Exemgel 7 2-Ftalímidoetansulfcn-N-(bensyl)etano1amíd Föreningen framställdes enligt exemplet 1 ur N-bensyletanolamin.The yield was 2.7 g (81%; theory, 3.34 g) mp = 134 DEG-136 DEG C. Example G 2 Phthalimidoethanesulfone-N- (4-carbomethoxybenzyl) amide The compound was prepared according to Example 1 from methyl 4-amino methylhensoate. Yield 3.0 g (75%; theory 4.02 g) Mp: 172 DEG-174 DEG C. Example 7 2-Phthalimidoethanesulfon-N- (benzyl) ethanolamide The compound was prepared according to Example 1 from N-benzylethanolamine.

Utbytet 2,0 g (52 %; teor. 3,9 g) Sp.: 92 - 94°C .458 606 U 14 Exe el 8 2-FtalimidoetansulfonflN-(4-karboxamidobensyl)amid Föreningen framställdes enligt exemplet 1 ur 4-aminomety1- bensamid. Utbytet 2,3 g (S8 %: teor. 3,9 g) sp.= 173 - 174°c Exemgel 9 2-Ftalímidoetansu1fon-N-(3-dimetylaminobensyl)amid Föreningen framställdes enligt exemplet 1 ur 3-âimetylamino- bensylamin. Utbytet 1,8 g (45 %; teor. 3,9 g) Sp.: 116 - ll8°C Exemgel 10 2-Ftalimidoetansulfon-N-(2,4-diklorbensyl)amid Föreningen framställdes enligt exemfilet 1 ur 2,4-diklor- bensylamin. Utbytet 2,9 g (71 %; teor. 4,1 g) sp.= 161 - 1s3°c Exempel ll 2-Ftalimídoetansulfon-N-(3-trifluormetylbensyl)amidÅ ' Föreningen framställdes enligt exemplet 1 ur 3-trifluormetyl- bensylamin. Utbytet 3,24 g (79 %: teør. 4,1 g) Sp.= 134 - l3S°C -l . _ 458 606 1s Exempel 12 2-Ftalímidoetansu1fon-N-(4-fluorbensyl)amíd Föreningen framställdes enligt exemplet l ur 4-fluørbensylamin.Yield 2.0 g (52%; theory 3.9 g) Mp: 92-94 ° C .458 606 U 14 Example 8 2-Phthalimidoethanesulfon fl N- (4-carboxamidobenzyl) amide The compound was prepared according to Example 1 from 4- aminomethyl1-benzamide. Yield 2.3 g (S8%: theory 3.9 g) mp = 173 DEG-174 DEG C. Example 9 2-Phthalimidoethanesulfon-N- (3-dimethylaminobenzyl) amide The compound was prepared according to Example 1 from 3-methylaminobenzylamine. Yield 1.8 g (45%; theory, 3.9 g) Mp: 116-118 ° C Example gel 2-Phthalimidoethanesulfon-N- (2,4-dichlorobenzyl) amide The compound was prepared according to Example 1 from 2,4- dichlorobenzylamine. Yield 2.9 g (71%; theory 4.1 g) mp = 161 DEG-163 DEG C. Example 11 2-Phthalimidoethanesulfone-N- (3-trifluoromethylbenzyl) amide The compound was prepared according to Example 1 from 3-trifluoromethylbenzylamine . Yield 3.24 g (79%: theory 4.1 g) Mp = 134 DEG-13 DEG C. 458 606 1s Example 12 2-Phthalimidoethanesulfon-N- (4-fluorobenzyl) amide The compound was prepared according to Example 1 from 4-fluorobenzylamine.

Utbytet 2,9 g (81 %; teor. 3,6 g) Sp.: 163 - l64°C Exempel 13 2-Fta1imidcetansu1fon-N-(3-fenyl)propy1amid Föreningen framställdes enligt exemplet 1 ur 3-fenylpropylamin.Yield 2.9 g (81%; theory, 3.6 g) Mp: 163 DEG-164 DEG C. Example 13 2-Phthalimide cetanesulfon-N- (3-phenyl) propylamide The compound was prepared according to Example 1 from 3-phenylpropylamine.

Utbytet 3,0 g (81 %; teor. 3,7 g) sp.= 117 - 119°c Exempel 14 2-Ftalimidoetansulfon-N-[3-(4-k1orfenyl)prøpyl]amid Föreningen framställdes enligt exemplet 1 ur 3-(4-klorfeny1)- prqpylamin. Utbytet 2,5 g (61 %; teor. 4,06 g) sp.= 151 - 1s2°c Exempel 15 2-Fta1imídoetansu1fon-N-[2-(4-dimetylsulfonamidofenyl)et§l]amid Föreningen framställdes enligt exemplet l ur N,N-dimety1-4- (2-aminoetyl)bensensu1fonamid. Utbytet 2,3 g (49 %; teor. 4,65 g) sp.= 110 - 114°c .e'4ss46o6 16 Exemgel 16 2-Ftalimidoetansulfon~N-I2-(3-dimetylaminofenyl)etyl]amid Föreningen framställdes enligt exempel l ur 2-(3-dimetylamino- feny1)etylamin. Utbytet 1,5 g (37 %; teor. 4,0 g) Sp.: 86 - 90°C Exemgel 17 2-Ftalimidoetansulfon-N-E3-(4-dímetylaminofenyl)propyl]amid Föreningen framställdes enligt exempel 1 ur 3-(4-dimetylamino- fenyl)propylamin. Utbytet 1,8 g (43 %: teor. 4,15 g).Yield 3.0 g (81%; theory 3.7 g) mp = 117-119 ° C Example 14 2-Phthalimidoethanesulfon-N- [3- (4-chlorophenyl) propyl] amide The compound was prepared according to Example 1 from 3 - (4-chlorophenyl) -propylamine. Yield 2.5 g (61%; theory 4.06 g) mp = 151-150 ° C Example 15 2-Phthalimidoethanesulfon-N- [2- (4-dimethylsulfonamidamidophenyl) ethyl] amide The compound was prepared according to Example 1 from N, N-dimethyl- 4- (2-aminoethyl) benzenesulfonamide. Yield 2.3 g (49%; theory, 4.65 g) mp = 110-114 ° C .4.46.46 Example 16 16-Phthalimidoethanesulfon-N-I2- (3-dimethylaminophenyl) ethyl] amide The compound was prepared according to Example 1 from 2- (3-dimethylaminophenyl) ethylamine. Yield 1.5 g (37%; theory 4.0 g) Mp: 86-90 ° C Example 17 2-Phthalimidoethanesulfon-N-E3- (4-dimethylaminophenyl) propyl] amide The compound was prepared according to Example 1 from 3- (4-dimethylaminophenyl) propylamine. Yield 1.8 g (43%: theory, 4.15 g).

Sp.: 90 - 94°C Exemgel l8 2-Ftalimidoetansu1fon-N-(4-metoxibensyl)amid Till en blandning bestående av 2-ftalimidoetansulfonamíd (0,0l mol), 50 ml toluen, 50 ml koncentrerad kaliumhydroxidlös- .ning och 0,1 g tetrabutylammoniumvätesulfat, sattes 0,012 mol 4-metoxibensylbromid. Blandningen omrördes i 30 timmar. Skiktena separerades och det organiska skiktet tvättades med vatten.Mp: 90 DEG-94 DEG C. Example 18 2-Phthalimidoethanesulfon-N- (4-methoxybenzyl) amide To a mixture consisting of 2-phthalimidoethanesulfonamide (0.01 mol), 50 ml of toluene, 50 ml of concentrated potassium hydroxide solution and , 1 g of tetrabutylammonium hydrogen sulfate, 0.012 mol of 4-methoxybenzyl bromide was added. The mixture was stirred for 30 hours. The layers were separated and the organic layer was washed with water.

Utbytet var 1,8 g (48 %: teor. 3,7 9).The yield was 1.8 g (48%: theory, 3.79).

Produktens smältpunkt motsvarade den i exemplet l angivna.The melting point of the product corresponded to that given in Example 1.

Exemgel 19 2-Fta1imidoetansulfon-N-(4-metoxibensyl)amíd Kaliumsalt av ftalimid (0,0l mol) och N-(4-metoxibensyl)-2- brometansulfonamid (0,06 mol) löstes i 70 ml dimetylformamid. 458 606 17 Lösningen värmdes vid 105 - ll0°C i 7 timmar. Till den avkylda lösningen sattes 150 ml vatten och den bildade stelnade oljan avskiljdes. Produkten kristalliserades ur vattenhaltig etanol.Example 19 2-Phthalimidoethanesulfon-N- (4-methoxybenzyl) amide Potassium salt of phthalimide (0.01 mol) and N- (4-methoxybenzyl) -2-bromethanesulfonamide (0.06 mol) was dissolved in 70 ml of dimethylformamide. The solution was heated at 105-110 ° C for 7 hours. To the cooled solution was added 150 ml of water, and the formed solidified oil was separated. The product was crystallized from aqueous ethanol.

Utbytet var 1,9 g (51 %; teor. 3,7 g).The yield was 1.9 g (51%; theory 3.7 g).

Produktens smältpunkt motsvarade den i exemplet 1 angivna.The melting point of the product corresponded to that given in Example 1.

Exemgel 20 2-Ftalimidoetansulfon-N-(Å-metylbensyl)amid En lösning av ftalsyraanhydrid (0,0l mol) och N-(4-metylbensyl)- 2-aminoetansulfonamid (0,0l5 mol) uppvärmdes vid 130 - l40°C i 2 timmar. Blandningen kyldes och löstes i en liten mängd het etanol. Vid nedkylningen av etanollösningen utkristalliserade produkten. Utbytet var 1,7 g (47 %; teor. 3,6 g).Example 2 2-Phthalimidoethanesulfon-N- (α-methylbenzyl) amide A solution of phthalic anhydride (0,01 mol) and N- (4-methylbenzyl) -2-aminoethanesulfonamide (0,05 mol) was heated at 130-140 ° C in 2 hours. The mixture was cooled and dissolved in a small amount of hot ethanol. Upon cooling the ethanol solution, the product crystallized out. The yield was 1.7 g (47%; theory, 3.6 g).

Vid användningen av ftalsyra (0,0l mol) som utgångsämne, uppvärmdes blandningen i 2 timmar vid ca 200°C och sulfonamid användes i överskott (0,03 mol). Utbytet var 1,1 g I (30 %: teor. 3,6 9).Using phthalic acid (0.01 mol) as a starting material, the mixture was heated for 2 hours at about 200 ° C and sulfonamide was used in excess (0.03 mol). The yield was 1.1 g I (30%: theory 3.6 9).

I båda fallena var produktens smältpunkt densamma som angivits för produkten i exempel 2In both cases, the melting point of the product was the same as that indicated for the product of Example 2

Claims (5)

I 458 eos 18 PatentkravI 458 eos 18 Patentkrav 1. 2-Ftalímidoetansulfon-N-arylamider, k ä n n e t e c k - n a d därav, att de har formeln I CO 'Rl N-cflz-cnz-soz-N- (eng )n-R2 (I) co ' där n = l - 4 och R1 är väte eller en alkyl~ eller hydroxialkylgrupp med 1 - 6 kolatomer RZ är a) R3 R4 där R3 och R4 kan yara_lika eller olika och avser väte, en a1k°Xí“f alkoxikarbonvl- eller alkylgrupp medlïv l - 4 kolatomer, halogen, trifluormetyl eller en nítrogrupp eller en grupp med formeln R5 R5 R5 -N : -S02N eller -CON \Rs Rs \ Rs där R5 och R5 kan oberoende av varandra avse väte eller en alkylgrupp med l - 4 kolatomer, men om n _ - 1 kan R1, R3 och R4 inte samtidigt avse en väteatomer, b) där Z = 0. N eller S. 458 192. 2-Phthalimidoethanesulfon-N-arylamides, characterized in that they have the formula I CO 'R 1 N-c fl z-cnz-soz-N- (eng) n-R 2 (I) co' where n = 1 - 4 and R 1 is hydrogen or an alkyl or hydroxyalkyl group having 1 to 6 carbon atoms R 2 is a) R 3 R 4 where R 3 and R 4 may be the same or different and refer to hydrogen, an alkoxycarbonyl or alkyl group having 1 to 4 carbon atoms , halogen, trifluoromethyl or a nitro group or a group of the formula R5 R5 R5 -N: -SO2N or -CON \ Rs Rs \ Rs where R5 and R5 may independently refer to hydrogen or an alkyl group having 1 to 4 carbon atoms, but if n - 1, R 1, R 3 and R 4 may not simultaneously refer to a hydrogen atom, b) where Z = 0. N or S. 458 2. Förfarande för framställning av fysiologiskt verksam 2-ftalimidoetansulfon-N-arylamid med formel I co al NH-cnzcnzsoz-N- ( C32 ) n-Rz ( 1 ) 'där n = l - 4 och R1 är väte eller en alkyl- eller hydroxialkylgrupp med 1 - 6 kolatomer Rz är a)_ R3 R4 åär R3 och R4 kan vara lika eller olika och avser väte, en alkoxi-, alkoxíkarbonyl- eller alkylgrupp med 1 - 4 kolatomer, halogen, trífluormetyl eller en nitrogrupp eller en grupp med formeln R I R R 5 z 5 z 5 ~$02N eller -CON Re Rs Rs 6:06 där R5 och R5 kan oberoenäe av varandra avse väte eller en alkylgrupp med 1 - 4 kolatomer, men om n = 1 kan RI, R3 och R4 inte samtidigt avse en väteatomer. b) \ 458 eos 20 där Z = O, N eller S, k ä n n e t e c k n a t därav, att 1) en ftalimidoetansulfonylkloríd med formeln II CO _ NH-cH-zcnzsozcl CO omsätts med en amín med formeln III 1.11 NH-(CH2)n-R2 där n, R1 och R2 avser det samma som ovan, 2) en ftalimidoetansulfonamíd med formel IV CO Rl 1 NH-CH2CH2SO2-NH CO \/ (II) (III) (IV) där R1 avser det samma som ovan, alkyleras med ett lämpligt alkyleringsmedel innehållande gruppen R2 avser det samma som ovan,A process for the preparation of physiologically active 2-phthalimidoethanesulfone-N-arylamide of formula I co al NH-cnzcnzsoz-N- (C32) n-Rz (1) 'where n = 1-4 and R 1 is hydrogen or an alkyl- or hydroxyalkyl group having 1 to 6 carbon atoms R 2 is a) - R 3 R 4 or R 3 and R 4 may be the same or different and refer to hydrogen, an alkoxy, alkoxycarbonyl or alkyl group having 1 to 4 carbon atoms, halogen, trifluoromethyl or a nitro group or group with the formula RIRR 5 z 5 z 5 ~ $ 02N or -CON Re Rs Rs 6:06 where R5 and R5 may independently refer to hydrogen or an alkyl group having 1 to 4 carbon atoms, but if n = 1, R1, R3 and R4 may does not at the same time refer to a hydrogen atom. b) wherein Z = O, N or S, characterized in that 1) a phthalimidoethanesulfonyl chloride of formula II CO - NH-cH-znzsozcl CO is reacted with an amine of formula III 1.11 NH- (CH2) n -R 2 where n, R 1 and R 2 denote the same as above, 2) a phthalimidoethanesulfonamide of formula IV CO R 11 NH-CH 2 CH 2 SO 2 -NH 2 CO 2 (II) (III) (IV) where R 1 denotes the same as above, with a suitable alkylating agent containing the group R 2 means the same as above, 3. ) en ftalimidoetansulfonamíd med formeln V CO H I NH-CH2CH2SO2-N-(CH2)n-R2 CO,/I -(CH2)n-R2, där n och (V) Ä 458 606 21 där n och R2 avser det samma som ovan, alkyleras med lämpligt alkyleringsmedel innehållande gruppen R1, som definierats ovan,3.) a phthalimidoethanesulfonamide of the formula V CO HI NH-CH 2 CH 2 SO 2 -N- (CH 2) n -R 2 CO, / I - (CH 2) n -R 2, where n and (V) are n and R 2 same as above, alkylated with the appropriate alkylating agent containing the group R 1, as defined above, 4. ) en ftalimid med formeln VI co\\ NH (VI) CO'/ eller dess salt omsätta med en förening med formeln VII R1 | x-cnzcngsogm- ( en; ) n-Rz (VII) där n, R1 och R2 avser det samma som ovan och X är en utbytbar grupp, såsom t.ex. halogen, eller4.) reacting a phthalimide of the formula VI with NH (VI) CO '/ or its salt with a compound of the formula VII R1 | x-cnzcngsogm- (en;) n-Rz (VII) where n, R1 and R2 refer to the same as above and X is a substitutable group, such as e.g. halogen, or 5. ) en ftalsyraanhydrid med formeln VIII CO\\\ o cof// (VIII) eller motsvarande syra omsätts med en amín med formeln IX R1 _ 1 ngn-cugcnzsozu-(cH2)n-R; (IX) där n, R1 och R2 avser det samma som ovan.5.) a phthalic anhydride of the formula VIII (COII) or the corresponding acid is reacted with an amine of the formula IX R1 - 1 ngn-cugcnzsozu- (cH2) n-R; (IX) where n, R1 and R2 denote the same as above.
SE8701524A 1987-04-10 1987-04-10 2-PHTALIMIDOETAN SULPHON-N-ARYLAMIDES AND PROCEDURES FOR PREPARING THESE SE458606B (en)

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SE8701524A SE458606B (en) 1987-04-10 1987-04-10 2-PHTALIMIDOETAN SULPHON-N-ARYLAMIDES AND PROCEDURES FOR PREPARING THESE
PCT/FI1988/000043 WO1988007991A1 (en) 1987-04-10 1988-03-29 Novel sulfonamides, a process for their preparation and pharmaceutical compositions containing these new sulfonamides
AU14994/88A AU1499488A (en) 1987-04-10 1988-03-29 Novel sulfonamides, a process for their preparation and pharmaceutical compositions containing these new sulfonamides
JP63502909A JPH02502996A (en) 1987-04-10 1988-03-29 Novel sulfonamides, processes for their preparation and pharmaceutical compositions containing these new sulfonamides
EP88902862A EP0355098A1 (en) 1987-04-10 1988-03-29 Novel sulfonamides, a process for their preparation and pharmaceutical compositions containing these new sulfonamides
FI894315A FI894315A0 (en) 1987-04-10 1989-09-13 NYA SULPHONAMIDER, FOERFARANDE FOER DERAS FRAMSTAELLNING OCH DESSA NYA SULFONAMIDER INNEHAOLLANDE PHARMACEUTICAL COMPOSITION.

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DE3718892A1 (en) * 1987-06-05 1988-12-22 Bayer Ag POLYHYDROBENZ (C, D) INDOLSULFONAMIDE
US5112866A (en) * 1988-09-06 1992-05-12 Ortho Pharmaceutical Corporation Ethanesulfonamide derivatives

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SE434638B (en) * 1980-06-06 1984-08-06 Lekemedelsfabriken Medica Ab NEW THERAPEUTIC WORLDFUL TAURIN DERIVATIVES AND THEIR PREPARATION

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SE8701524D0 (en) 1987-04-10
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EP0355098A1 (en) 1990-02-28
AU1499488A (en) 1988-11-04
SE8701524L (en) 1988-10-11

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