NO162664B - Nye 1,2,5-tiadiazolderivater. - Google Patents

Nye 1,2,5-tiadiazolderivater. Download PDF

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NO162664B
NO162664B NO86862501A NO862501A NO162664B NO 162664 B NO162664 B NO 162664B NO 86862501 A NO86862501 A NO 86862501A NO 862501 A NO862501 A NO 862501A NO 162664 B NO162664 B NO 162664B
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alkyl
independently
amino
alkoxy
phenyl
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NO162664C (no
NO862501D0 (no
NO862501L (no
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Ronnie Ray Crenshaw
Aldo Antonio Algieri
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Bristol Myers Co
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
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Abstract

Hittil ukjente mellomprodukter til anvendelse ved fremstilling av 3,4-disubstituert-l,2,5-tiadiazol-1-oksyder og -1,1-dioksyder har formlene. hvor R er bl.a. halogen, alkoksy eller fenyltio,. er a(CH,) Z(CH,) NH-, RRN- eller HS(CH-) NH, hvor R og R bl.a er hydrogen eller en alkylgruppe.

Description

Burimamid (a) var den første klinisk effektive H^-reseptorantagonist. Det inhiberer sekresjon i magen hos dyr og mennesker, men oral absorpsjon er liten.
Metiamid (b), som er en senere undersøkt I^-antagonist, er
kraftigere enn burimamid og er oralt aktiv i mennesker. Den kliniske anvendbarhet var imidlertid begrenset på grunn av gift-
ighet (agranulocytose). Cimetidin (c) er en like effektiv E^-
antagonist som metiamid uten å fremkalle agranulocytose, og den er nylig markedsført som et antiulcus-legemiddel. Halveringstiden for cimetidin er forholdsvis kort, og den nødvendiggjør derfor en terapeutisk kur med flere daglige doser av 200-300 mg. tabletter.
Det er således behov for antiulcus-midler som er lengre virkende og/eller kraftigere enn cimetidin.
Den foreliggende oppfinnelse vedrører hittil ukjente mel-
lomprodukter til anvendelse ved fremstilling av 3,4-disubstitu-ert-1,2,5-tiadiazol-l-oksyder og -1,1-dioksyder med formelen
hvor p er 1 eller 2,
1 2 3
R er hydroksy eller NR R ,
2 3
R og R hver for seg uavhengig av hverandre er hydrogen, (C1-C12)alkyl, (C3-Cg)alkenyl, (C3-Cg)alkynyl, cyklo(C3-Cg)alkyl, cyklo(C3-C6)alkyl(C1-C2)alkyl, hydroksy(C^g)alkyl, (C-j-Cg)-alkoksy(C1-Cg)alkyl, pyridyl (C^-Cg ) alkyl, amino, hydroksy, (Cl"C6)alkoksy' 2'3_dihydroksyProPy1' A'-(CH2)m,Z,~(CIVn,~' fenyl (C-^-Cg) alkyl eller substituert fenyl(C^-Cg)alkyl, hvor fenylringen inneholder en metylendioksysubstituent under den for-2 3
utsetning av R og R ikke begge er cyklo(C3~Cg)alkyl, substituert fenyl, amino, hydroksy, (C,-C,)alkoksy eller A'-(CH_) , Z'-2 3 (CH2)n,-, eller R og R sammen med N-atomet er en pyrrolidono-, morfolino- eller piperidinoring,
m og rn' er hver uavhengig av hverandre et helt tall 0-2,
n og n<*> er hver uavhengig av hverandre et helt tall 2-4, ;Z og Z' er hver uavhengig av hverandre svovel eller oksygen, eller kan være -CH_- når A er ;5-dimetylammometyl-2-furyl og R 1 er amino, som eventuelt er substituert med en (C^-C^)alkylgruppe. ;A og A' er hver uavhengig av hverandre, fenyl, imidazolyl, tiazolyl, furyl, tienyl eller pyridyl, under den forutsetning av at A og A' uavhengig av hverandre kan inneholde én eller to sub-stituenter, idet den første substituent er valgt blant (C1 ,-CD,)-alkyl, amino, ;og den andre er valgt blant (C^-Cg)alkyl og amino, ;q er et helt tall 0-3, begge R er uavhengig av hverandre hydrogen, (C^-Cg)alkyl eller (C-^-Cg)alkanoyl, eller de to R <4->grupper sammen kan være etylen, og ;R og R hver er uavhengig av hverandre hydrogen, (C^-Cg)-alkyl, (C1-Cg)alkenyl eller (C^-Cg)alkynyl eller R<5> og RD kan sammen med det nitrogenatom som de er bundet til være pyrro-lidino, morfolino, piperidino, metylpiperidino, N-metylpiperazino eller homopiperidino, ;eller et ikke-toksisk, farmasøytisk akseptabelt salt, hydrat, solvat eller N-oksyd derav. ;Oppfinnelsen vedrører hittil ukjente mellomprodukter med formelen ;hvor p er 1 eller 2, ;R 7 er (C^tC^)alkoksy, og ;R1<2> er A(CH2) Z(CH2) NH-, R2R<3>N- eller HS(CH2)nNH-, hvor R<2 >og R3 hver uavhengig av hverandre er hydrogen, (C^-C^2)alkyl, (C3-Cg)alkenyl, (C3-<C>g)alkynyl, cyklo(C3-Cg)alkyl, cyklo(C3~C6)-alkyl(C1-C2)alkyl, hydroksy(C1-Cg)alkyl, (C1-Cg)alkoksy(C1-Cg)-alkyl, pyridyl(C1-Cg)alkyl, amino, hydroksy, (^-Cg)alkoksy, 2,3-dihydroksypropyl, A" - (CH2) , Z • (CH2 ) n,-, fenyl (C^-Cg) alkyl, eller substituert fenyl(C,-Cfi)alkyl hvor fenylringen inneholder en .23 metylendioksysubstituent under den forutsetning at R og R ikke begge er cyklo(C3~Cg)alkyl, substituert fenyl, amino, hydroksy, (C1-<C>g)alkoksy eller A'-(CH2)m,Z'(CH2)n,-, eller R<2> og R<3> er sammen med N-atomet en pyrrolidin-, morfolin- eller piperidin-ring, ;m og m' er hver uavhengig av hverandre et helt tall 0-2, ;n og n' er hver uavhengig av hverandre et helt tall 2-4, ;Z og Z<*> er hver uavhengig av hverandre svovel eller oksygen, eller kan vare metylen når A er 5-dimetylaminometyl-2-furyl,
A og A' er hver uavhengig av hverandre fenyl, imidazolyl, tiazolyl, furyl, tienyl eller pyridyl, under den forutsetning at A og A' uavhengig av hverandre kan inneholde én eller to sub-stituenter, idet den første substituent er valgt blant (C^-Cg)-alkyl, amino,
og den annen er valgt blant (C^-Cg)alkyl og amino,
q er et helt tall 0-3,
begge R 4 er uavhengig av hverandre hydrogen, (C,-Cg)alkyl eller (C1~Cg)alkanoyl, eller de to R 4-grupper kan sammen være etylen, og
R og R^ hver er uavhengig av hverandre hydrogen, (C,-C,)-5 6 alkyl, (C3~C6)alkenyl eller (C3-Cg)alkynyl, eller R og R kan sammen med det nitrogenatom som de er bundet til være pyrroli-dino, morfolino, piperidino, metylpiperidino, N-metylpiperazino eller homopiperidino,
eller salt, hydrat, solvat eller N-oksyd derav.
Det har vist seg at mange av de her fremstilte forbindelser med formelen I kraftig holder tilbake løsningsmidler som de er krystillisert fra. I noen tilfeller viser det seg at produktene er ekte solvater, mens produktene i andre tilfeller bare holder tilbake ekstra løsningsmiddel eller er en blanding av solvat og noe ekstra løsningsmiddel. Selv om løsningsmidlet kan fjernes ved tørking ved høyere temperatur, forandrer dette ofte et pent krystallinsk produkt til et gummiaktig fast stoff. Idet de solvatiserte produkter vanligvis har temmelig skarpe smelte-punkter, er det vanlig praksis å tørke produktene ved romtem-peratur. Når det blir holdt tilbake løsningsmiddel selv etter langvarig tørking, bestemmes mengden løsningsmiddel, f.eks. ved NMR. De nedenfor anførte eksempler angir mengden løsningsmiddel (der hvor det er egnet), og analysene og smeltepunktene gjelder for det solvatiserte produkt dersom ikke noe annet er angitt.
Eksempel 1
3- { 2- C( 5- metyl- lH- imidazol- 4- yl)- metyltio] - etylamino}-4- metoksy- l, 2, 5- tiadiazol- l, 1- dioksyd
Til en godt. omrørt suspensjon av 2,0 g (11,2 mmol) 3,4-dimetoksy-1, 2,5-tiadizol-l,.l-dioksyd (fremstilt ved fremgangs-måten ifølge J. Org. Chem., Vol 40, 1975, p. 2743) i 200 ml metanol ved omgivelsestemperatur ble det tilsatt en løsning av 2,73 g (fra dihydrokloridet, 11,2 mmol) av 2-[(5-metyl-lH-imidazol-4-yl)-metyltio]-etylamin (fremstilt ifølge belgisk patentskrift 779.775) i 25 ml metanol. Etter omrøring i 30 minutter fremkom det en metanolisk løsning av tittelforbindelsen. Tynnsjiktskromatografi (silisiumoksyd/CH2Cl2:CH30H (90:10)) ga Rf = 0,44.
Eksempel 2
3- { 2-[( 5- dimetylaminometyl- 2- furyl)- metylticQ - etylamino}-4- metoksy- l, 2, 5- tiadiazol- l, 1- dioksyd
En løsning av 2,14 g (10,0 mmol) av 2-[(5-dimetylaminometyl-2-furyl)-metyltioj -etylamin i 25 ml tørr metanol ble dråpevis tilsatt i løpet av 35 minutter til en godt omrørt suspensjon av 1,78 g (10,0 mmol) av 3,4-dimetoksy-l,2,5-tiadiasol-l,1-dioksyd i 180 ml tørr metanol, som var blitt avkjølt til 1°C i et is-vannbad. Etter 15 minutter ved 0°C hadde det dannet seg en metanolløsning av tittelforbindelsen. Tynnsjiktskromatografi (silisiumoksyd/CH2Cl2:CH30H = 9:1) ga Rf = 0,48.
En 2,0 ml aliguot av løsningen ble surgjort med 6,ON HC1 og inndampet under senket trykk uten oppvarming til dannelse av tittelforbindelsen som hydrokloridsaltet. NMR-spektret (100 MHZ) i D20 ga følgende resonanser «: 6,45 (d, 1H), 6,19 (d, 1H), 4,14 (s, 2H), 4,0 (s, 3H), 3,64 (s, 2H), 3,37 (t, 2H), 2,65 (s, 6H), 2,61 (t, 2H).
Eksempel 3
3- {2-["( 5- dimetylaminometyl- 2- furyl)- metyltioj- etylamino}-4- metoksy- l, 2, 5- tiadiazol- l- oksyd
En løsning av 3,30 g (15,4 mmol) av 2-\_{ 5-dimetylaminometyl-2-furyl)-metyltio]-etylamin i 25 ml metanol ble dråpevis tilsatt i løpet av 14 minutter til en godt omrørt suspensjon av 2,50 g (15,4 mmol) av 3,4-dimetoksy-l,2,5-tiadiazol-l-oksyd som var avkjølt til 12-15°C i et is-vannbad. Løsningen ble omrørt ved omgivelsestemperatur i 1,5 timer til dannelse av metanolisk løsning av tittelforbindelsen.

Claims (1)

1,2,5-tiadiazolderivater, karakterisert
ved at den har formelen
hvor p er 1 eller 2, R er (C^-C^)alkoksy, og R12 er A(CH_) Z(CH_) NH-, R2R3N- eller HS(CH-) NH-, hvor R2 og R hver uavhengig av hverandre er hydrogen, (C^-C.^2) alkyl, (C3-Cg)alkenyl, (C3-Cg)alkynyl, cyklo(C3-Cg)alkyl, cyklo (C-j-Cg) - alkyl (C1-C2) alkyl, hydroksy (C^-Cg ) alkyl, (C^-Cg ) alkoksy (^-Cg ) - alkyl, pyridyl(C^-Cg)alkyl, amino, hydroksy, (C^-Cg)alkoksy, 2,3-dihydroksypropyl, A'-{CH2) ,Z*(CH2) ,-, fenyl(C^-Cg)alkyl, eller substituert fenyl(C.-C,)alkyl hvor fenylringen inneholder en .23 metylendioksysubstituent under den forutsetning at R og R ikke begge er cyklo(C3~Cg)alkyl, substituert fenyl, amino, hydroksy, (C,-C,)alkoksy eller A'-(CH_) ,Z'(CH_) ,-, eller R<2> og R3 er 16 2 m zn sammen med N-atomet en pyrrolidin-, morfolin- eller piperidin-ring, m og m' er hver uavhengig av hverandre et helt tall 0-2, n og n' er hver uavhengig av hverandre et helt tall 2-4, Z og Z' er hver uavhengig av hverandre svovel eller oksygen, eller kan være metylen når A er 5-dimetylaminometyl-2-fury.l, A og A' er hver uavhengig av hverandre fenyl, imidazolyl, tiazolyl, furyl, tienyl eller pyridyl, under den forutsetning at A og A' uavhengig av hverandre kan inneholde én eller to sub-stituenter, idet den første substituent er valgt blant (C]_-Cg)~ alkyl, amino,
og den annen er valgt blant (C^-Cg)alkyl og amino,
q er et helt tall 0-3,
begge R 4 er uavhengig av hverandre hydrogen, (C^-Cg) alkyl eller (C1~Cg)alkanoyl, eller de to R<4->grupper kan sammen være etylen, ogR^ og R^ hver er uavhengig av hverandre hydrogen, (C,-Cfi)-alkyl, (C3-Cg)alkenyl eller (C-j-Cg) alkynyl, eller R <5> og R° 6kan sammen med det nitrogenatom som de er bundet til være pyrroli-dino, morfolino, piperidino, metylpiperidino, N-metylpiperazino eller homopiperidino,
eller salt, hydrat, solvat eller N-oksyd derav.
NO86862501A 1979-09-04 1986-06-23 Nye 1,2,5-tiadiazolderivater. NO162664C (no)

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US7251779A 1979-09-04 1979-09-04
US11718280A 1980-01-31 1980-01-31
US16383180A 1980-06-07 1980-06-07

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NO162664B true NO162664B (no) 1989-10-23
NO162664C NO162664C (no) 1990-01-31

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NO80802576A NO160003C (no) 1979-09-04 1980-09-02 Analogifremgangsmaate til fremstilling av terapeutisk aktive 3,4-disubstituerte 1,2,5-tiadiazol-1-oksyder og -1,1-dioksyder.
NO86862501A NO162664C (no) 1979-09-04 1986-06-23 Nye 1,2,5-tiadiazolderivater.
NO87871420A NO161737C (no) 1979-09-04 1987-04-06 1,2,5-tiadiazolderivater.
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