DK164700B - 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider - Google Patents

3,4-disubstituerede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider Download PDF

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DK164700B
DK164700B DK269090A DK269090A DK164700B DK 164700 B DK164700 B DK 164700B DK 269090 A DK269090 A DK 269090A DK 269090 A DK269090 A DK 269090A DK 164700 B DK164700 B DK 164700B
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alkyl
amino
phenyl
alkoxy
hydroxy
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DK269090A
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DK269090D0 (da
DK164700C (da
DK269090A (da
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Aldo Antonio Algieri
Ronnie Ray Crenshaw
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Squibb Bristol Myers Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/24—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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
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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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Lubricants (AREA)

Description

i
DK 164700 B
Den foreliggende opfindelse angår hidtil ukendte 3,4-disubstitue-rede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider, der er nyttige som mellemprodukter ved fremstillingen af de i dansk patentansøgning nr.
3718/80 (svarende til fremlæggelsesskrift nr. 160.611 B) omhandlede 5 histamin ^-antagonister.
Disse histamin Hg-antagonister, som er nyttige til behandling af sygdommen peptisk ulcer, har formlen (O) p 10 ^s\
N N
M1 ‘ A-(CH2)raZ(CH2)nNH R1 hvori 15 p betegner 1 eller 2, 1 2 3 R betegner hydroxy eller NR R , 2 3 R og R hver især uafhængigt af hinanden betegner hydrogen, (lavere)al kyl, (lavere)alkenyl, (lavere)alkynyl, cyclo(1avere)-alkyl, cyclo(lavere)alkyl(lavere)alkyl, hydroxy(lavere)al kyl, (lavere)-20 alkoxy(lavere)al kyl, (lavere)alkylthio(lavere)alkyl, amino(lavere)al kyl, (lavere)al kyl amino(lavere)al kyl, di(lavere)al kyl amino(lavere)al kyl, pyrroli di no(1avere)alky1, p i peri d i no(1avere)al kyl, morpholi no(1avere)-alkyl, piperazino(lavere)alkyl, pyridyl(lavere)al kyl, amino, (lavere)-alkylamino, di(lavere)al kyl amino, 2,2,2-trifluorethyl, 2-fluorethyl, 25 hydroxy, (lavere)alkoxy, 2,3-dihydroxypropyl, cyano, cyano(lavere)-alkyl, amidino, (lavere)alkylamidino, A'-iCfy^Z'(CH2)n/-, phenyl, phenyl(lavere)al kyl, substitueret phenyl eller substitueret phenyl -(lavere)al kyl, hvori phenylringen kan indeholde en eller to substi-tuenter uafhængigt valgt blandt (1avere)al kyl, hydroxy, (lavere)-30 alkoxy og halogen eller en substituent valgt blandt methyl endioxy, 2
trifluormethyl og di(lavere)alkylamino, under den forudsætning at R
3 og R ikke begge er cyclo(lavere)al kyl, phenyl, substitueret phenyl, amino, (lavere)alkyl amino, di(lavere)alkylamino, hydroxy, (lavere)-alkoxy, cyano, amidino, (lavere) al kyl amid i no eller A'-iCHg)^ 35 Z'(CH2)n,-, eller R2 og R3 betegner tilsammen -CHgCHgXiCHg)^, r er et helt tal fra 1 til 3, inklusive, 4 X betegner methylen, svovl, oxygen eller N-R under den forudsætning, at når r er 1, er X methylen,
DK 164700B
2 4 R betegner hydrogen, (lavere)al kyl, (lavere)alkenyl, (lavere)-alkynyl, (lavere)alkanoyl eller benzoyl, m og m' er hver især uafhængigt af hinanden et helt tal fra O til 2, inklusive, 5 n og n' er hver især uafhængigt af hinanden et helt tal fra 2 til 4, inklusive, Z og V er hver især uafhængigt af hinanden svovl, oxygen eller methyl en, A og A' er hver især uafhængigt af hinanden phenyl, imidazolyl, 10 thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazo-lyl, oxadiazolyl, furyl, thienyl eller pyridyl, under den forudsætning at A og A' uafhængigt af hinanden kan indeholde en eller to substi-tuenter, idet den første substituent er udvalgt blandt (lavere)alkyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl, (lavere)-15 alkoxy, -(CH2)qN=C og -(CH2)qNR5R6 20 og den anden er udvalgt blandt (lavere)al kyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl og (lavere)alkoxy, q er et helt tal fra 0 til 6, inklusive, begge R er uafhængigt af hinanden som ovenfor defineret, eller de to R4-grupper kan tilsammen 25 betegne ethylen, og 5 6 R og R betegner hver især uafhængigt af hinanden hydrogen, (lavere) - alkyl, (lavere) al kenyl, (lavere) al kynyl, cycl o (lavere) al kyl eller phenyl, under den forudsætning at R og R ikke begge kan være 5 6 cyclo(lavere)al kyl eller phenyl, eller R og R kan sammen med det 30 nitrogenatom, hvortil de er knyttet, betegne pyrrolidino, morpholino, piperidino, methyl piperidino, N-methylpiperazino eller homopiperidino, eller et ikke-toxisk, farmaceutisk acceptabelt salt, hydrat, solvat eller N-oxid deraf.
De 3,4-disubstituerede 1,2,5-thiadiazol-l-oxider og -1,1-dioxider 35 ifølge opfindelsen har den almene formel (XVII) 3
DK 164700 B
(0)P
N N XVII
M
5 HS(CH2)nH/ NR2R3 hvori p er 1 eller 2, n er et helt tal fra 2 til 4, inklusive, 2 3 10 R og R hver især uafhængigt af hinanden betegner hydrogen, (lavere)- alkyl, (lavere)alkenyl, (lavere)alkynyl, cyclo(lavere)al kyl, cyclo- (lavere)alkyl(lavere)alkyl, hydroxy(lavere)al kyl, (lavere)alkoxy- (1avere)alky1, (1 avere)al kylth i o(1avere)al kyl, ami no(1avere)al kyl, (1avere)al kyl ami no(1avere)al kyl, di(1avere)al kyl ami no(1avere)al kyl, 15 pyrrolidino(lavere)alkyl, piperidino(lavere)alkyl, morpholino(lavere)- alkyl, piperazino(lavere)alkyl, pyridyl(lavere)al kyl, amino, (lavere)- alkyl amino, di(lavere)al kyl ami no, 2,2,2-tri fluorethyl, 2-fluorethyl, hydroxy, (lavere)alkoxy, 2,3-dihydroxypropyl, cyano, cyano(lavere)al kyl, amidino, (lavere)alkylamidino, A'-tCHgJ^Z'(CH2)n/-, phenyl, phenyl- 20 (lavere)al kyl, substitueret phenyl eller substitueret phenyl(lavere)- alkyl, hvori phenylringen kan indeholde én eller to substituenter uafhængigt udvalgt blandt (lavere)alkyl, hydroxy, (lavere)alkoxy og halogen, eller én substituent udvalgt blandt methyl endioxy, trifluor- 2 3 methyl og di(lavere)alkylamino, under den forudsætning at R og R ikke 25 begge kan være cyclo(lavere)al kyl, phenyl, substitueret phenyl, amino, (lavere)alkyl amino, di(lavere)al kyl amino, hydroxy, (lavere)alkoxy, cyano, amidino, (lavere)alkylamidino eller A'-(CH2)m,Z'(CH2)n/-> eller R^ og R3 kan tilsammen betegne -CHgCHgXiCHjJp-, r er et helt tal fra 1 til 3, inklusive, 4 30 X betegner methylen, svovl, oxygen eller N-R , under den forudsætning, at når r er 1, betegner X methylen, R* betegner hydrogen, (1avere)al kyl, (1avere)alkenyl, (1avere)alkynyl, (lavere)alkanoyl eller benzoyl, m' er et helt tal fra 0 til 2, inklusive, 35 n' er et helt tal fra 2 til 4, inklusive, 1' betegner svovl, oxygen eller methylen, A' betegner phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, iso-xazolyl, triazolyl, thi adi azolyl, oxadiazolyl, furyl, thienyl eller
DK 164700 B
4 pyridyl, under den forudsætning at A' kan indeholde en eller to substi-tuenter, idet den første substituent er udvalgt blandt (lavere)alkyl, · hydroxy, trifluormethyl, halogen, amino, hydroxymethyl, (lavere)alkoxy, 5 NHR4 -(CH2>qN=CC^ °9 -(CH2)qNR5R6 NHR4 og den anden er udvalgt blandt (lavere)alkyl, hydroxy, trifluormethyl, 10 halogen, amino, hydroxymethyl og (lavere)alkoxy, q er et helt tal fra O til 6, inklusive, 4 hvert R er uafhængigt af hinanden som ovenfor defineret, eller de to 4 R -grupper kan tilsammen betegne ethyl en, og 5 6 R og R betegner hver især uafhængigt af hinanden hydrogen, (lavere)- 15 al kyl, (lavere) alkenyl, (lavere)alkynyl, cyclo(lavere)alkyl eller 5 6 phenyl, under den forudsætning at R og R ikke begge kan være cyclo- 5 6 (lavere)al kyl eller phenyl, eller R og R kan sammen med det nitrogenatom, hvortil de er knyttet, betegne pyrrolidino, morpholino, piperi-dino, methyl piperidino, N-methylpiperazino eller homopiperidino, 20 eller et salt, hydrat, solvat eller N-oxid deraf.
Forbindelserne med formlen I kan fremstilles ud fra en forbindelse med formlen XVII via den i reaktionsskemaet nedenfor anførte reaktionsvej.
Omsætningerne udføres i et inert organisk opløsningsmiddel. Det har 25 vist sig, at methanol er et hensigtsmæssigt og let tilgængeligt opløsningsmiddel. Reaktionstemperaturen er ikke kritisk. De fleste udgangsmaterialer er temmelig reaktive, og det foretrækkes at udføre omsætningen ved en temperatur under stuetemperatur, f.eks. 0-10°. Med nogle mindre reaktive forbindelser er det hensigtsmæssigt at udføre 30 omsætningen ved stuetemperatur. Undertiden er det ønskeligt senere at hæve reaktionsblandingens temperatur (f.eks. til 50-60°) for at fuldende omsætningen.
5
DK 164700 B
(O) p /sv
Reaktionsskema „ x ---- N n M, R7 R7
II
/R10H \^S(CH2)nHH2 (0)p (0)p
NN N N
W // \\J
R7 R10 HS(CH2)n!IH R7 χ„ XI11 \ / \hS(CH_) NH- / \ 2 n 2 /r10h (0) /s\
N N
\\ // ^
1 / ^ R10 HS(CH2)nNH K
A(CH2)mX
V
(0)p /S\ K.
A(CH-) S(CH-) NH R
λ m i n I c 6
DK 164700 B
I reaktionsskemaet betegner en let fraspaltelig gruppe udvalgt blandt halogen, (lavere)alkoxy, (lavere)alkylthio, phenoxy eller phenylthio, som kan indeholde 1 eller 2 substituenter udvalgt blandt 10 2 3 halogen, (lavere)al kyl, (lavere)alkoxy og nitro, R -NR R , og X er en 5 konventionel fraspaltelig gruppe. Egnede fraspaltelige grupper omfatter f.eks. fluor, chlor, brom, iod, -O^SR^, hvori R** betegner (lavere)-alkyl (f.eks. methansulfonat), aryl eller substitueret aryl (f.eks. benzensul fonat, p-brombenzensulfonat eller p-toluensul fonat), O^SF, acetoxy og 2,4-dinitrophenoxy. Af nemheds og økonomiske grunde fore-10 trækkes det at anvende en forbindelse, hvori X betegner chlor. Omsætningen af forbindelsen med formlen XVII med AiCHg)^ kan udføres i et hvilket som helst inert organisk opløsningsmiddel, såsom en alkanol, acetonitril, dimethyl formamid, dimethyl sulfoxid, acetone, og lignende.
Det foretrækkes at udføre omsætningen i en alkanol, såsom methanol, 15 ethanol eller isopropanol. Reaktionstemperaturen er ikke kritisk; omsætningen kan udføres ved temperaturer på fra ca. 0° til ca. 200°C. Ved lave temperaturer er omsætningen langsom, medens høje temperaturer normalt fører til mindre rene produkter på grund af nedbrydning og dannelse af biprodukter. Det foretrækkes sædvanligvis at udføre omsæt-20 ningen ved stuetemperatur. Omsætningen af forbindelsen med formlen XVII med AiCHgJrøX til dannelse af forbindelsen med formlen Ic udføres fortrinsvis i nærværelse af en base, som letter omsætningen ved at optræde som en syreacceptor. Egnede baser omfatter f.eks. NaOH, KOH, LiOH, triethylamin, dimethylanilin, natriumethoxid, og lignende. Hvor X 25 betegner hydroxyl, kan omsætningen udføres i koncentreret mineral syre, f.eks. HC1. Alle mellemprodukter med formlen XIII, XIV og XVII er hidtil ukendte forbindelser.
Eksempel 1 30 3-methyl ami no-4-(2-mercaptoethylami no)-1,2,5-th i adi azol-1,1-di oxi d Eh opløsning af 2-aminoethanthiol (fra hydrochloridet 1,91 g, 16,8 mmol) i 20 ml methanol sattes dråbevis i løbet af en periode på 15 minutter til en godt omrørt suspension af 3,4-dimethoxy-l,2,5--thiadiazol-l,l-dioxid (3,0 g, 16,8 mmol) i 250 ml methanol, der var 35 blevet afkølet til 1° i et is-vandbad. Efter 10 minutter ved 2-4° bob-ledes methylamin til den afkølede opløsning i 6 minutter, og omrøring fortsattes i yderligere 30 minutter ved omgivelsernes temperatur. Reaktionsblandingen inddampedes under formindsket tryk, og remanensen 7
DK 164700 B
anbragtes på 45 g silicagel og kromatograferedes under anvendelse af en gradienteluering af methylenchlorid-methanol. De relevante fraktioner forenedes og inddampedes, og produktet (2,43 g) krystalliseredes fra absolut ethanol. Omkrystallisation fra absolut ethanol gav titelfor-5 bindeisen, snip. 259-260° (dek.).
Analyse for C5Hjo^402S2:
Beregnet: C: 27,03, H: 4,54, N: 25,20,
Fundet: C: 27,13, H: 4,55, N: 24,86.
10 Eksempel 2 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thi adi azol-1-oxid
En opløsning af 2-aminoethanthiol (fra hydrochloridet, 2,04 g, 18,0 mmol) i 25 ml methanol sattes dråbevis i løbet af en periode på 30 minutter til en godt omrørt suspension af 3,4-dimethoxy-l,2,5-15 -thiadiazol-l-dioxid (2,92 g, 18,0 mmol) (fremstillet ifølge eksempel 4, trin A) i 150 ml methanol, der var blevet afkølet til 3° i et is--vandbad. Efter 10 minutter bobledes vandfri methylamin til opløsningen i 6 minutter, og omrøring fortsattes ved omgivelsernes temperatur i yderligere 20 minutter. Reaktionsblandingen inddampedes 20 under reduceret tryk, og remanensen anbragtes på 45 g silicagel og kromatograferedes under anvendelse af en gradienteluering af methy-lenchlorid-methanol. De relevante fraktioner forenedes og inddampedes til dannelse af 2,74 g af produktet. Omkrystallisation fra methanol og derpå 95% ethanol gav titel forbindel sen, smp. 191-193°.
25
Eksempler på fremstillingen af slutforbindelser med formlen (I) ud fra forbindelser ifølge opfindelsen.
Eksempel 3 30 3-(2-((5-dimethylaminomethyl-2-furyl)methylthio1ethylamino)-4-methylamino-l,2,5-thiadiazol-l,l-dioxid
En blanding indeholdende 3-methylamino-4-(2-mercaptoethylamino)- l,2,5-thiadiazol-l,l-dioxid (1,0 g, 4,5 mmol) (fremstillet i eksempel 1) og 5-dimethylaminomethyl-2-furanmethanol (0,82 g, 4,5 mmol) (fremstillet 35 i henhold til den i J. Chem. Soc., 4728 (1958) beskrevne fremgangsmåde) i 20 ml koncentreret saltsyre omrørtes i et is-vandbad i 2 timer og henstod derefter ved 0° i 64 timer. Reaktionsblandingen omrørtes ved omgivelsernes temperatur under reduceret tryk, og remanensen deltes 8
DK 164700 B
mellem vand og methylenchlorid. Den vandige fase gjordes basisk med natriumbicarbonat og ekstraheredes med methylenchlorid. Den forenede organiske fase vaskedes med mættet saltvandsopløsning, tørredes og inddampedes under reduceret tryk. Remanensen anbragtes på 25 g silicagel 5 og kromatograferedes under anvendelse af en gradieneluering af methylenchlorid-methanol. Den relevante fraktion inddampedes, og produktet krystalliseredes fra methanol. Omkrystallisation fra methanol gav titel forbindel sen, smp. 92-96°.
10 Eksempel 4 3-(2-Γ(5-dimethylaminomethyl-2-furyl)methyl hi olethyl amino)-4-methyl -amino-1,2,5-thiadiazol-l-oxid Når 3-methyl amino-4-(2-mercaptoethylamino)-1,2,5-thiadiazol-l-oxid (fremstillet i eksempel 2) behandles med ca. 1 ækvivalent 5-dimethyl ami-15 nomethyl-2-furanmethanol i koncentreret saltsyre i henhold til den i eksempel 3, beskrevne fremgangsmåde fås titel forbindel sen; identisk med produktet ifølge eksempel 13. Smp. 86-92°C.
Analyse for
Beregnet: C: 45,46, H: 6,16, H: 20,39, S: 18,67.
20 Fundet: C: 45,24, H: 6,24, N: 20,41, S, 18,90.

Claims (1)

  1. 9 DK 164700 B 1. 3,4-disubstitueret 1,2,5-thiadiazol-1-oxid eller -1,1-oxid med formlen 5 p /> H us(Oi2)nm nrV hvori p er 1 eller 2, n er et helt tal fra 2 til 4, inklusive, 2 3 R og R hver især uafhængigt af hinanden betegner hydrogen, (1avere)- 15 al kyl, (lavere)alkenyl, (lavere)alkynyl, cyclo(lavere)al kyl, cyclo- (lavere)alkyl(lavere)alkyl, hydroxy(lavere)alkyl, (lavere)alkoxy- (lavere)al kyl, (lavere)al kyl thio(lavere)al kyl, amino(lavere)al kyl, (lavere)al kyl amino(lavere)al kyl, di(lavere)alkylamino(lavere)alkyl, pyrrol i d i no(1avere)al kyl, p i peri di no(1avere)alky1, morpholi no(1avere)- 20 alkyl, piperazino(lavere)alkyl, pyridyl(lavere)al kyl, amino, (lavere)- alkylamino, di(lavere)al kyl amino, 2,2,2-trifluorethyl, 2-fluorethyl, hydroxy, (lavere)alkoxy, 2,3-dihydroxypropyl, cyano, cyano(lavere)al kyl, amidino, (lavere)al kyl amidi no, A/'(CH2)ni/Z,(CH2)n/-, phenyl, phenyl- (lavere)al kyl, substitueret phenyl eller substitueret phenyl(lavere)- 25 al kyl, hvori phenylringen kan indeholde én eller to substituenter uafhængigt udvalgt blandt (lavere)al kyl, hydroxy, (lavere)alkoxy og halogen, eller én substituent udvalgt blandt methyl endioxy, trifluor- 2 3 methyl og di(1averejalkyl amino, under den forudsætning at R og R ikke begge kan være cyclo(lavere)al kyl, phenyl, substitueret phenyl, amino, 30 (lavere)al kyl amino, di(lavere)al kyl ami no, hydroxy, (lavere)alkoxy, cyano, amidino, (lavere)alkylamidino eller A,-(CH2)m,Z/(CH2)n,-, eller R^ og R^ kan tilsammen betegne -CH2CH2X(CH2)r-, r er et helt tal fra 1 til 3, inklusive, X betegner methylen, svovl, oxygen eller N-R4, under den forudsætning, 35 at når r er 1, betegner X methylen, R4 betegner hydrogen, (1avere)al kyl, (1avere)alkenyl, (1avere)alkynyl, (lavere)alkanoyl eller benzoyl, m' er et helt tal fra 0 til 2, inklusive, 10 DK 164700 B n' er et helt tal fra 2 til 4, inklusive, V betegner svovl, oxygen eller methyl en, A' betegner phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, iso-xazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl eller 5 pyridyl, under den forudsætning at A' kan indeholde en eller to substi-tuenter, idet den første substituent er udvalgt blandt (lavere)alkyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl, (lavere)alkoxy, ^—-NHR4 10 -(CH2^qN=CC^ °9 -(CH2)qNR5R6 NHR^ og den anden er udvalgt blandt (lavere)alkyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl og (lavere)alkoxy, 15. er et helt tal fra O til 6, inklusive, hvert R er uafhængigt af hinanden som ovenfor defineret, eller de to 4 R -grupper kan tilsammen betegne ethyl en, og 5 6 R og R betegner hver især uafhængigt af hinanden hydrogen, (lavere)- alkyl, (lavere) alkenyl, (lavere) al kynyl, cycl o (lavere) al kyl eller 20 phenyl, under den forudsætning at R og R ikke begge kan være cyclo- 5 6 (lavere)alkyl eller phenyl, eller R og R kan sammen med det nitrogenatom, hvortil de er knyttet, betegne pyrrolidino, morpholino, piperi-dino, methyl piperidino, N-methylpiperazino eller homopiperidino, eller et salt, hydrat, sol vat eller N-oxid deraf. 25 30 35
DK269090A 1979-09-04 1990-11-09 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider DK164700C (da)

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GB2132190B (en) 1985-01-03
NL9201237A (nl) 1993-03-01
NO871421D0 (no) 1987-04-06
IE51235B1 (en) 1986-11-12
US4374248A (en) 1983-02-15
DK268990A (da) 1990-11-09
FI76795B (fi) 1988-08-31
NO160781C (no) 1989-05-31
GB8318949D0 (en) 1983-08-17
CA1248962A (en) 1989-01-17
CA1263115A (en) 1989-11-21
MY8700735A (en) 1987-12-31
DK160611C (da) 1991-09-16
DK164702C (da) 1992-12-21
DE3033169A1 (de) 1981-03-19
PT71764A (en) 1980-09-30
SE456581B (sv) 1988-10-17
CH649764A5 (de) 1985-06-14
AR240559A1 (es) 1990-05-31
GB2067987A (en) 1981-08-05
DK269190A (da) 1990-11-09
FI76795C (fi) 1988-12-12
NO161737B (no) 1989-06-12
CS235951B2 (en) 1985-05-15
SG61187G (en) 1987-10-23
DK269190D0 (da) 1990-11-09
NO160003C (no) 1989-03-01
NO160781B (no) 1989-02-20
DK269090A (da) 1990-11-09
LU82753A1 (fr) 1981-04-17
AT376978B (de) 1985-01-25
KE3685A (en) 1987-01-30
IE861175L (en) 1981-03-04
CY1360A (en) 1987-08-07
IE50997B1 (en) 1986-09-03
DK164702B (da) 1992-08-03
DK268990D0 (da) 1990-11-09

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