DK164702B - 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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DK164702B
DK164702B DK269190A DK269190A DK164702B DK 164702 B DK164702 B DK 164702B DK 269190 A DK269190 A DK 269190A DK 269190 A DK269190 A DK 269190A DK 164702 B DK164702 B DK 164702B
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alkyl
phenyl
alkoxy
independently
avere
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DK269190A
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DK164702C (da
DK269190D0 (da
DK269190A (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
    • 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
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-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
    • C07D271/10—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
    • 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
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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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 164702 B
Den foreliggende opfindelse angår hidtil ukendte 3,4-disubstitue-rede 1,2,5-thiadiazol-l-oxider eller -1,1-dioxider, der er nyttige som mellemprodukter ved fremstillingen af de i dansk patentansøgning nr.
3718/89 (svarende til fremlæggelsesskrift nr. 160.611 B) omhandlede 5 histamin Hg-antagonister.
Disse histamin Hg-antagonister er nyttige til behandling af sygdommen peptisk ulcer og har formlen (O) p /s\
10 N N I
M, A_(CH2)rnZ(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, (1avere)-alkyl, (lavere)alkenyl, (lavere)alkynyl, cyclo(lavere)al kyl, cyclo-(1avere)al kyl(1avere)al kyl, hydroxy(1avere)al kyl, (1avere)al koxy-20 (1avere)al kyl, (lavere)alkylthio(lavere)alkyl, amino(lavere) al kyl, (lavere)al kyl ami no(1avere)al kyl, di(1avere)al kylamino(lavere) al kyl, pyrrol i di no(1avere)al kyl, pi peri di no(1avere)al kyl, morpholi no(1 avere) -alkyl, piperazino(lavere)al kyl, pyridyl(lavere)al kyl, amino, (lavere)-alkylamino, di(lavere)alkylamino, 2,2,2-trifluorethyl, 2-fluorethyl, 25 hydroxy, (lavere)alkoxy, 2,3-dihydroxypropyl, cyano, cyano(lavere)-alkyl, amidino, (lavere) al kyl amid i no, A'- (0Η2)ιη/Ζ/ (CH2)n,-, phenyl, phenyl(lavere)al kyl, substitueret phenyl eller substitueret phenyl -(lavere)alkyl, hvori phenylringen kan indeholde en eller to substi-tuenter uafhængigt valgt blandt (lavere)al kyl, hydroxy, (lavere)-30 alkoxy og halogen eller en substituent valgt blandt methylendioxy, 2
trifluormethyl og di(lavere)alkyl amino, under den forudsætning at R
3 og R ikke begge er cyclo(lavere)al kyl, phenyl, substitueret phenyl, amino, (lavere)al kyl amino, di(lavere)al kyl amino, hydroxy, (lavere)-alkoxy, cyano, amidino, (lavere)al kylamidino eller A'-(CH9)m, 35 Z'fCHgJp/-» eller R^ og R·3 betegner tilsammen -CHgCHgXiCHg)^.-, r er et helt tal fra 1 til 3, inklusive, X betegner methylen, svovl, oxygen eller N-R^ under den forudsætning, at når r er 1, er X methylen, 4
DK 164702 B
2 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 methylen, A og A' er hver især uafhængigt af hinanden phenyl, imidazolyl, 10 thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl eller pyridyl, under den forudsætning at A og A' uafhængigt af hinanden kan indeholde en eller to substituenter, idet den første substituent er udvalgt blandt (lavere)al kyl , hydroxy, trifluormethyl, halogen, amino, hydroxymethyl, (lavere)alkoxy, 15 NHR4 -(CH2)qN=CC^^ og -(CH2)qNR5R6 ^NHR4 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 R4 er uafhængigt af hinanden som ovenfor defineret, eller de to R4-grupper kan tilsammen betegne ethyl en, og 25 R og R betegner hver især uafhængigt af hinanden hydrogen, (lavere)-, alkyl, (lavere)alkenyl, (lavere)alkynyl, cyclo(lavere)alkyl eller phenyl, under den forudsætning at R og R ikke begge kan være cycl o-(lavere)al kyl eller phenyl, eller. R og R kan sammen med det nitrogenatom, hvortil de er knyttet, betegne pyrrolidino, morpholino, piperi-30 dino, methylpiperidino, N-methylpiperazino eller homopiperidino, eller et ikke-toxisk, farmaceutisk acceptabelt salt, hydrat, sol vat eller N-oxid deraf.
De 3,4-disubstituerede 1,2,5-thiadiazol-l-oxider eller -1,1* dioxider har den almene formel (XVI) 35 (0)p
DK 164702 B
3
Vjf XVI
5 B12/\R7 hvori p er 1 eller 2, R^ betegner en fraspaltelig gruppe udvalgt blandt halogen, (1avere)-alkoxy, (lavere)al kyl thio, phenoxy, phenylthio, substitueret phenoxy og 10 substitueret phenylthio, hvori phenylringen kan indeholde 1 eller 2 substituenter udvalgt blandt halogen, (lavere)alkyl, (lavere)alkoxy og nitro, og R12 betegner A(CH2)mZ(CH2)nNH-, R2R3N- eller HS(CH2)nNH-, hvori R2 og R3 hver især uafhængigt af hinanden betegner hydrogen, (lavere)al kyl, 15 (lavere)alkenyl, (lavere)alkynyl, cyclo(lavere)al kyl, cyclo(lavere)-alkyl(lavere)al kyl, hydroxy(lavere)alkyl, (lavere)alkoxy(lavere)al kyl, (1 avere) al ky 11 h i o (1 avere) al kyl, ami no (1 avere) al kyl, (1 avere) al kyl ami noil avere) al kyl, di(lavere)alkylaraino(lavere)alkyl, pyrrolidino(lavere)-alkyl, piperidino(lavere)alkyl, morpholino(lavere)alkyl, piperazino-20 (lavere)al kyl, pyridyl(lavere)al kyl, amino, (lavere)al kyl amino, di(lavere)alkyl amino, 2,2,2-tri fluorethyl, 2-fluorethyl, hydroxy, (lavere)alkoxy, 2,3-dihydroxypropyl, cyano, cyano(lavere)al kyl, amidino, (lavere)alkylamidino, A'-(CH2)m,Z/(CH2)n,-, phenyl, phenyl(lavere)-alkyl, substitueret phenyl eller substitueret phenyl(lavere)al kyl, hvori 25 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, trifluormethyl og di(lavere)-al kyl amino, under den forudsætning at R og R ikke begge kan være cyclo(lavere)al kyl, phenyl, substitueret phenyl, amino, (lavere)al kyl -30 amino, di(lavere)al kyl amino, hydroxy, (lavere)alkoxy, cyano, amidino, (lavere)alkylamidino eller A,-(CH2)n)/Z'(CH2)n/-, eller R2 og R3 kan tilsammen betegne -CH2CH2X(CH2)r-, r er et helt tal fra 1 til 3, inklusive, X betegner methylen, svovl, oxygen eller N-R^, under den forudsætning, 35 at når p er 2, og R betegner methoxy, kan R og R sammen med det nitrogen, hvortil de er knyttet, ikke betegne morpholino, og at når r er 1, betegner X methylen, 4 R betegner hydrogen, (lavere)al kyl, (1avere)alkenyl, (lavere)alkynyl,
DK 164702B
4 (lavere)alkanoyl eller benzoyl, m og m' er hver især uafhængigt af hinanden et helt tal fra O til 2, inklusive, n og n' er hver især uafhængigt af hinanden et helt tal fra 2 til 4, 5 inklusive, Z og V er hver især uafhængigt af hinanden svovl, oxygen eller methylen, A og A' er hver især uafhængigt af hinanden phenyl, imidazolyl, thia-zolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, 10 oxadiazolyl, furyl, thienyl eller pyridyl, under den forudsætning at A og A' uafhængigt af hinanden kan indeholde en eller to substituenter, idet den første substituent er udvalgt blandt (lavere)alkyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl, (lavere)alkoxy, 15 NHR4 -(CH2)qN=C*C^ og -(CH2)qNR5R6 NHR4 og den anden er udvalgt blandt (lavere)al kyl, hydroxy, trifluormethyl, 20 halogen, amino, hydroxymethyl og (lavere)alkoxy, q er et helt tal fra 0 til 6, inklusive, 4 hvert R er uafhængigt af hinanden som ovenfor defineret, eller de to 4 R -grupper kan tilsammen betegne ethylen, og 5 6 R og R betegner hver især uafhængigt af hinanden hydrogen, (lavere)- 25 alkyl, (lavere) alkenyl, (lavere)alkynyl, cycl o (lavere) al kyl 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 nitrogen-• atom, hvortil tfe er knyttet, betegne pyrrolidino, morpholino, piperi-dino, methyl piperidino, N-methylpiperazino eller homopiperidino, 30 eller salt, hydrat, sol vat eller N-oxid deraf.
Forbindelserne med formlen I kan fremstilles ud fra en forbindelse med formlen XVI som vist i reaktionsskemaet nedenfor.
35
DK 164702 B
5
Reaktionsskema 1 (0) p
5 (°}P A (CH_) Z (CH_) NH_ ^ XN
- > ^^ A(CH2)mZ(CH2)nNH R7 R7 · R?
II
9 q
R H RyH
Ψ M
(0)o (o) .
/s\ /-s\
N N A(CH,) Z(CH,) NH, N N
,H. - ^ K
R7 R A(CH2)mZ(CH2) NH R
XVI-b la 1 2 3
Note: R = -NR κ
DK 164702 B
6 I reaktionsskema 1 udføres omsætningerne i et inert organisk opløsningsmiddel. Det har 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 5 udføre omsætningen ved en temperatur under stuetemperatur, f.eks. 0-10°.
Med nogle mindre reaktive forbindelser er det hensigtsmæssigt at udføre omsætningen ved stuetemperatur. Undertiden er det ønskeligt senere at hæve reaktionsblandingens temperatur (f.eks. til 50-60°) for at fuldende omsætningen.
10
DK 164702 B
7 T?eaktionsskema_2. · (0)p
Forbindelse aICH^Z (CH-, ) „NH., ΐζ \ m.a
A(CH„) Z(CH~) NH R
2. ru 2 Ti (0)p /S\ u A(CH2)mZ(CH2)nNH Ib 0 5
DK 164702 B
8 I reaktionsskema 2 betegner M en metal kation, som fortrinsvis er K+, Li+ eller Na+. Reaktionsbetingelserne og opløsningsmidlerne er som beskrevet for reaktionsskema 1.
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9 R'eaklionsskema 3
Forbindelse
II
\HS(CH-) NH-\ 2 n 2 (0)p /S\
N N
\\ // XVI-c /“Λ 7
HS(CK_) NH R
2 n
^/r^H
(°)p /S\
N N
}-{ / N _10
HS(CH_) NH R
2 n
A(CH2)mX
7x K,
A(CH0) S(CH_) NH R
λ m l n
Ic
DK 164702 B
10 10 2 3 I reaktionsskema 3 betegner R -NR R , og X er en konventionel fraspaltelig gruppe. Egnede fraspaltelige grupper omfatter f.eks. fluor, chlor, brom, iod, -OgSR^, hvori R^ betegner (lavere)alkyl (f.eks. methansulfonat), aryl eller substitueret aryl (f.eks. benzen-sulfonat, 5 p-brombenzensulfonat ell^r p-toluensulfonat), O^SF, acetoxy og 2,4- dinitrophenoxy. Af nemheds og økonomiske grunde foretrækkes det at anvende en forbindelse, hvori X betegner chlor. Reaktionsbetingelserne for fremstillingen af forbindelserne med formlerne XVI-c og XV er som beskrevet for reaktionsskema 1. Omsætningen af forbindelsen med formlen 10 XV med A(CH2)mX 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, ethanol eller isopropanol. Reaktionstemperaturen er ikke kritisk; omsætningen kan udføres ved temperaturer på fra 15 ca. 0° til ca. 200°C. Ved lave temperat.urer 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 omsætningen ved stuetemperatur. Omsætningen af forbindelsen med formlen XV med A(CH2)mX til dannelse af forbindelsen 20 med formlen I c 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, dimethyl anil in, natriumethoxid, og lignende. Hvor X betegner hydroxyl, kan omsætningen udføres i koncentreret mineralsyre, f.eks. HC1. Alle mellemprodukter med formlen XVI-c 25 og XV er hidtil ukendte forbindelser.
Opfindelsen belyses i det følgende nærmere.
30 35
DK 164702 B
11
Eksempel 1 3-(2-r(5-methyl-lH-imidazol-4-yl)methy1thioleth,ylamino')-4-methoxy- 1.2.5- thiadiazol-1,1-dioxid
Til en godt omrørt iuspension af 3,4-dimethoxy-l,2,5-thiadiazol-5 1,1-dioxid (2,0 g, 11,2 mmol) (fremstillet i henhold til den i J. Org.
Chem., 40, 2743 (1975) beskrevne fremgangsmåde) i 200 ml methanol ved omgivelsernes temperatur sattes en opløsning af 2-[(5-methyl-1H-imidazol-4-yl)-methylthio]ethylamin (fra dihydrochloridet, 2,73 g, 11,2 mmol) (fremstillet i henhold til belgisk patentskrift nr. 779.775) 10 i 25 ml methanol. Efter omrøring i 30 minutter fremkom en methanolisk opløsning af titelforbindelsen. TLC (silica/CHgCl2iCH^OH (90:10)) gav Rf = 0,44.
Eksempel 2 15 3-(2-r(5-dimethylaminoethyl-2-furyl )methyl thiol ethyl amino)-4-methox.y- 1.2.5- thiadiazol-1,1-dioxid
En opløsning af 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethyl-amin (2,41 g, 11,2 mmol) (fremstillet i henhold til den i belgisk patentskrift nr. 857.388 beskrevne fremgangsmåde) i 20 ml tør methanol 20 sattes på én gang til en godt omrørt, kold (8°) suspension af 3,4-di-methoxy-l,2,5-thiadiazol-l,l-dioxid (2,0 g, 11,2 mmol) i 200 ml methanol. Efter omrøring ved 8-10° i 15 minutter fremstilledes en methanolisk opløsning af titel forbindel sen.
25 Eksempel 3 3-(2-r(5-dimethy1aminomethyl-2-furyl)methylthiolethylaminol-4-methoxy- 1.2.5- thiadiazol-1,1-dioxid
En opløsning af 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethyl-amin (2,14 g, 10,0 mmol) i 25 ml tør methanol sattes dråbevis i løbet af 30 35 minutter til en godt omrørt suspension af 3,4-dimethoxy-l,2,5-thia-diazol-1,1-dioxid (1,78 g, 10,0 mmol) i 180 ml tør methanol, som var blevet afkølet til 1° i et i s-vandbad. Efter 15 minutter ved 0° fremkom en methanol-opløsning af titel forbindel sen. En TLC (si 1 i caiCHgClg:CH^OH (9:1)) gav Rf = 0,48.
35 En 2,0 ml aliquot af opløsningen gjordes sur med 6,ON HC1 og ind dampedes under reduceret tryk uden opvarmning til dannelse af titel forbindelsen som hydrochloridsaltet. NMR-spektret (100 MHz) i DgO gav følgende resonanser S: 6,45 (d, IH), 6,19 (d, IH), 4,14 (s, 2H), 4,0 (s,
DK 164702 B
12 3H), 3,64 (s, 2H), 3,37 (t, 2H), 2,65 (s, 6H), 2,61 (t, 2H).
Eksempel 4 3-f2-r(5-dimeth,yl aminomethyl-2-furyl)methylthioleth,yl aminoM-methoxy-5 1,2,5-thiadiazol-l-oxid
En opløsning af 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethyl-amin (3,30 g, 15,4 mmol) i 25 ml methanol sattes dråbevis i løbet af 14 minutter til en godt omrørt suspension af 3,4-dimethoxy-l,2,5-thia-diazol-l-oxid (2,50 g, 15,4 mmol) (fremstillet i henhold til den i 10 eksempel 4, trin A, beskrevne fremgangsmåde), der var afkølet til 12-15° i et is-vandbad. Opløsningen omrørtes ved omgivelsernes temperatur i 1,5 time til dannelse af en methanolisk opløsning af titel forbindel sen.
Eksempler på anvendelse af de 3,4-disubstituerede 1,2,5-thiadiazol-15 1-oxider eller -1,1-dioxider ifølge opfindelsen til fremstilling af slutforbindelser med formlen (I)
Eksempel 5 3-(2-r(5-methy1-lH-lmidazol-4-yl)methylthiolethylaminol-4-(2-propynyl)-20 amino-l,2,5-thiadiazol-l,l-dioxid
Til den methanol iske opløsning af produktet ifølge eksempel 1 sattes 7 ml 2-propynylamin. Efter omrøring ved omgivelsernes temperatur i 20 minutter inddampedes reaktionsblandingen under reduceret tryk, og den tilbageblevne olie anbragtes på si 1 i cage! og kromatograferedes ved 25 gradienteluering under anvendelse af methylenchlorid-methanol. De relevante fraktioner forenedes til dannelse af 2,74 g af titel forbindel sen som en olie.
En yderligere rensning opnåedes ved at forene det ovenfor nævnte materiale med det, der opnåedes i et identisk andet forsøg, og blan-30 dingen anbragtes på silicagel og kromatograferedes ved gradienteluering under anvendelse af methylenchlorid-methanol. De relevante fraktioner forenedes med methanol og inddampedes under reduceret tryk til dannelse af titelforbindelsen (2,93 g) som et letsmuldrende faststof, smp. 82-103°. NMR-spektrum (100 MHz) i dg dimethyl sulfoxid viste tilstedeværel-35 sen af 1/3 mol methanol.
Analyse beregnet for C: 42,19, H: 4,97, N: 23,95, S: 18,27,
Fundet: C: 42,05, H: 5,05, N: 24,01, S: 18,45.
DK 164702 B
13
Eksempel 6 3-{2-[(5-dimeth.y1 aminomethyl -2-fur.yl )methy1thio]ethy1 amino)-4-meth,yl-amino-l,2,5-thiadiazol-l,l-dioxid og 3,4-bis-f2-i(5-dimethylaminoroethyl-2-furyl)methy1thio1ethyl amino)-l,2,5-thiadiazo1 -1,1-dioxid 5 A. 3-f2“r(5-dimethy1aminoethyT-2-furyl)methyHhio1ethyl amino)-4-methylami no-1,2,5-thi adiazol-1,1-di oxi d
Vandfri methylamin bobledes til den afkølede (1°) methanoliske opløsning af produktet ifølge eksempel 2 i 6 minutter. Omrøring fortsat-10 tes i 10 minutter, og blandingen inddampedes under reduceret tryk.
Remanensen anbragtes på 45 g silicagel og kromatograferedes under anvendelse af gradienteluering af methylenchlorid-methanol. De relevante fraktioner, under anvendelse af methylenchlorid-methanol (95:5) forenedes i methanol, filtreredes gennem "Cel i te" og koncentreredes derpå 15 under reduceret tryk til dannelse af produktet. Omkrystalli sation fra methanol gav titelforbindelsen (1,76 g), smp. 82-90°. NMR-spektret (100 MHz) i dg dimethyl sul foxid viste tilstedeværelsen af 2/3 mol methanol.
Analyse beregnet for .Z/SCH^OH: C: 43,10, H: 6,26, N: 18,38, S: 16,83, 20 Fundet: C: 43,30, H: 6,12, N: 18,57, S: 16,96.
B. 3,4-bis-f2-r(5-dimethylaminometh.yl-2-fur.yl )methylthiolethyl amino)- 1,2,5-thiadiazol-1,1-di oxid
Den langsommere elueringskomponent under anvendelse af methylen-25 chlorid-methanol (9:1) fra kromatografien ifølge trin A anbragtes på 45 g aluminiumoxid og kromatograferedes under anvendelse af en gradienteluering af ethylacetat-methanol. Den relevante fraktion inddampedes, og remanensen tritureredes under ether-acetonitril til dannelse af et farveløst faststof, som opsamledes ved filtrering til dannelse af titel -30 forbindelsen (428 mg) som et monohydrat, smp. 92,5-96°.
Analyse beregnet for C22H.34NgS3O4.H2O: C: 47,12, H: 6,47, N: 14,99, S: 17,15,
Fundet: C: 47,28, H: 6,48, N: 15,09, S: 17,39.
Beregnet for HgO = 3,21% 35 Fundet = 3,32%.
DK 164702B
14
Eksempel 7 3-(2-r(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino)-4-hydroxy- 1,2,5-thi adi azol-1,1-di oxid
Til den methanoliske opløsning af produktet ifølge eksempel 3, 5 afkølet til 0° i et is-vandbad, sattes en opløsning af natriumhydroxid-pellets (2,10 g, 52,5 mmol) i 25 ml tør methanol. Efter omrøring ved 0° i 2 timer og ved omgivelsernes temperatur i 68 timer neutraliseredes reaktionsblandingen med 8,75 ml (52,5 mmol) vandig 6,ON HC1 og inddampedes under formindsket tryk efter 10 minutters omrøring. Remanensen 10 krystalliseredes under 95% EtOH til dannelse af det rå produkt, som opløstes i methanol, filtreredes til fjernelse af natriumchlorid, anbragtes på 60 g silicagel og kromatograferedes under anvendelse af en gradienteluering af methylenchlorid-methanol. De relevante fraktioner forenedes og inddampedes under reduceret tryk til dannelse af 3,19 g af 15 produktet. Omkrystallisation fra vandig methanol gav titel forbindelsen, smp. 109-122°.
Analyse beregnet for ci2^18^4°4S2: C: 41,61, H: 5,24, N: 16,17, S: 18,51,
Fundet (korrigeret for 1,15% HgO): 20 C: 41,59, H: 5,32, N: 16,33, S: 18,81.
Eksempel 8 3-(2-Γ(5-dimethylami nomethyl-2-furyl)methy!thiolethyl ami nol-4-methyl -amino-1,2,5-thiadiazol-1-oxid 25 Til den methanoliske opløsning af produktet ifølge eksempel 4, der var afkølet til 5° i et is-vand bad sattes vandfri methylamin i 8 minutter. Reaktionsblandingen omrørtes ved omgivelsernes temperatur i 17 timer, derefter inddampedes under reduceret tryk til dannelse af produktet som en gul olie, der anbragtes på 55 g silicagel og kromatografe-30 redes under anvendelse af en gradienteluering af methylenchlorid-methanol. Den relevante fraktion inddampedes, opløstes i methanol og fortyndedes med diethylether til dannelse af titel forbindel sen (2,32 g) som et faststof, der tørredes i vakuum ved omgivelsernes temperatur over PgOg i 3 timer, smp. 86-92°.
35 Analyse beregnet for ci3H21N5°2S2: C: 45,46, H: 6,16, N: 20,39, S: 18,67,
Fundet: C: 45,24, H: 6,24, N: 20,41, S: 18,90.

Claims (2)

  1. DK 164702 B 15 1. 3,4-disubstitueret 1,2,5-thiadiazol-l-oxid eller -1,1-dioxid med formi en (0)D 5 M R12/ - R7 10 hvori p er 1 eller
  2. 2, R7 betegner en fraspaltelig gruppe udvalgt blandt halogen, (lavere)-alkoxy, (lavere)al kylthio, phenoxy, phenyl thio, substitueret phenoxy og substitueret phenylthio, hvori phenylringen kan indeholde 1 eller 2 15 substituenter udvalgt blandt halogen, (lavere)al kyl, (lavere)alkoxy og nitro, og R12 betegner A(CH9) Z(CH,)nNH-, R2R3N- eller HS(CH9)nNH-, hvori R* og hver især uafhængigt af hinanden betegner hydrogen, (lavere)alkyl, (lavere)alkenyl, (lavere)alkynyl, cyclo(lavere)alkyl, 20 cycl o(lavere)al kyl(lavere)al kyl, hydroxy(lavere)alkyl, (lavere)alkoxy-(1 avere) al kyl, (1 avere) al kyl thi o (1 avere) al kyl, ami no (1 avere) al kyl, (1 avere) al kyl ami no (1 avere) al kyl, di (1 avere) al kyl ami no (1 avere) al kyl, pyrrol i di no(1avere)al kyl, pi peri di no(1avere)al kyl, morpholi no(1avere)-alkyl, piperazino(lavere)alkyl, pyridyl(lavere)alkyl, amino, (lavere)-25 alkylamino, di(lavere)al kyl amino, 2,2,2-tri fluorethyl, 2-fluorethyl, hydroxy, (lavere)alkoxy, 2,3-dihydroxypropyl, cyano, cyano(lavere)al kyl, amidino, (lavere)alkylamidino, Α'-ίΟΙ^^/Ζ'ίΟ^ρ/-, phenyl, phenyl-(1avere)al kyl, substitueret phenyl eller substitueret phenyl(lavere)-alkyl, hvori phenylringen kan indeholde én eller to substituenter 30 uafhængigt udvalgt blandt (lavere)al kyl, hydroxy, (lavere)alkoxy og halogen, eller én substituent udvalgt blandt methyl endioxy, trifluor-methyl og di(lavere)al kyl amino, under den forudsætning at R og R ikke begge kan være cyclo(1avere)al kyl, phenyl, substitueret phenyl, amino, (lavere)alkylamino, di(lavere)alkylamino, hydroxy, (lavere)alkoxy, 35 cyano, amidino, (lavere)alkylamidino eller A'-(CH9)_,Z'(CH9)n,-, eller R^ og R·5 kan tilsammen betegne -CHgCHgX(CHg)r-, r er et helt tal fra 1 til 3, inklusive, 4 X betegner methylen, svovl, oxygen eller N-R , under den forudsætning, 16 DK 164702 B 7 9 3 at når p er 2, og R betegner methoxy, kan R og R sammen med det nitrogen, hvortil de er knyttet, ikke betegne morpholino, og at når r er 1, betegner X methyl en, R^ betegner hydrogen, (lavere)al kyl, (lavere)alkenyl, (lavere)alkynyl, 5 (lavere)alkanoyl eller benzoyl, m og m' er hver især uafhængigt af hinanden et helt tal fra O til 2, inklusive, n og n' er hver især uafhængigt af hinanden et helt tal fra 2 til 4, inklusive, 10. og V er hver især uafhængigt af hinanden svovl, oxygen eller methyl en, A og A' er hver især uafhængigt af hinanden phenyl, imidazolyl, thia-zolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl eller pyridyl, under den forudsætning at A 15 og A' uafhængigt af hinanden kan indeholde en eller to substituenter, idet den første substituent er udvalgt blandt (lavere)al kyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl, (lavere)alkoxy, ^NHR4 20 -(CH«)rtN=C og -(CH0) NR5R6 c h λ c g og den anden er udvalgt blandt (lavere)al kyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl og (lavere)alkoxy, 25. er et helt tal fra 0 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, (1avere)alkynyl, cyclo(lavere)al kyl eller 30 phenyl, under den forudsætning at R^ og R® ikke begge kan være cyclo-(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 salt, hydrat, sol vat eller N-oxid deraf. 35
DK269190A 1979-09-04 1990-11-09 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider DK164702C (da)

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IE50997B1 (en) 1986-09-03
NO871420D0 (no) 1987-04-06
NL189197B (nl) 1992-09-01
CY1360A (en) 1987-08-07
NO160003C (no) 1989-03-01
CA1263114A (en) 1989-11-21
DK164702C (da) 1992-12-21
GB2067987A (en) 1981-08-05
CY1402A (en) 1987-12-18
DK269190D0 (da) 1990-11-09
ATA443480A (de) 1984-06-15
IE801851L (en) 1981-03-04
AR240559A1 (es) 1990-05-31
SE8006148L (sv) 1981-04-15
NL9201237A (nl) 1993-03-01
DK164363B (da) 1992-06-15
DK164363C (da) 1992-11-02
HK41387A (en) 1987-06-05
SE8403108L (sv) 1984-06-08
NO160003B (no) 1988-11-21
SE8403111L (sv) 1984-06-08
CH649764A5 (de) 1985-06-14
DE3033169A1 (de) 1981-03-19
SG61187G (en) 1987-10-23
CA1263115A (en) 1989-11-21
GB2067987B (en) 1984-07-11
NO161737B (no) 1989-06-12
NO802576L (no) 1981-03-05
NO862501L (no) 1987-03-05
DK371880A (da) 1981-03-05
GB2132190B (en) 1985-01-03
DK164700B (da) 1992-08-03
GB8318949D0 (en) 1983-08-17
DK269190A (da) 1990-11-09
LU82753A1 (fr) 1981-04-17
SE449099B (sv) 1987-04-06
CS235951B2 (en) 1985-05-15
AT377257B (de) 1985-02-25
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KE3742A (en) 1987-09-04
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NO162664C (no) 1990-01-31
MY8700585A (en) 1987-12-31
NO160781C (no) 1989-05-31
CA1167841A (en) 1984-05-22
FI802740A7 (fi) 1981-03-05
SE8403108D0 (sv) 1984-06-08
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PT71764B (en) 1983-04-28
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PT71764A (en) 1980-09-30
GB2132190A (en) 1984-07-04
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FI76795B (fi) 1988-08-31
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NO871421D0 (no) 1987-04-06
ZW20580A1 (en) 1981-01-21
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DE3051146C2 (de) 1991-05-02

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