DK155669B - Analogifremgangsmaade til fremstilling af pleuromutilinderivater - Google Patents

Analogifremgangsmaade til fremstilling af pleuromutilinderivater Download PDF

Info

Publication number
DK155669B
DK155669B DK004280AA DK4280A DK155669B DK 155669 B DK155669 B DK 155669B DK 004280A A DK004280A A DK 004280AA DK 4280 A DK4280 A DK 4280A DK 155669 B DK155669 B DK 155669B
Authority
DK
Denmark
Prior art keywords
compound
spectrum
amino
triazol
alkyl
Prior art date
Application number
DK004280AA
Other languages
English (en)
Other versions
DK155669C (da
DK4280A (da
Inventor
Heinz Berner
Friederike Turnowsky
Georg Laber
Johannes Hildebrandt
Original Assignee
Sandoz Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of DK4280A publication Critical patent/DK4280A/da
Publication of DK155669B publication Critical patent/DK155669B/da
Application granted granted Critical
Publication of DK155669C publication Critical patent/DK155669C/da

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having 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
    • C07D237/18—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/14—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
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D277/16—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • 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
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Description

i
DK 155669 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af forbindelser med den almene formel I
N-N
OC°CH2S —IL. Jj— y O “3 1 ch3 oh i hvor R betegner ethyl eller vinyl; 5 Y betegner hydrogen, amino, trifluormethyl, C-j^-alkyl, pyridyl eller -N(R3)(R4); 3 4 Z betegner hydrogen, _^-alkylsulfonyl, amino, formyl, -N(R )(R ), -S(CH0) N(R3)(R4) eller CX.NHR6; A n R3 og R4 har samme eller forskellig betydning, og hver betegner hy-10 drogen, _^-alkanoyl, der eventuelt er substitueret med alkoxysulfo-nyl; C-j^-alkylsulfonyl eller C^-alkyl; 6 R betegner C-j^-alkyl eller C^-alkoxycarbonyl; n betegner 2-5; og X betegner oxygen eller svovl,
15 eller syreadditionssalte eller kvaternære ammoniumsalte deraf, hvilken fremgangsmåde er ejendommelig ved, at en forbindelse med den almene formel II
2
DK 155669B
OCOCH2R^
Λ ch7 I
O 3 φ·”·\ί CH3 Oli 1 “i hvor R har den ovenfor anførte betydning, og R betegner chlor, brom eller -OSC>2R7, hvor R7 betegner alkyl eller aryl, omsættes med
en forbindelse med den almene formel III
N-N
5 hs —11 Jl—* 1,1 t z hvor Y og Z har den ovenfor anførte betydning, og en vunden forbindelse med formlen I, om ønsket, omdannes til et syreadditionssalt eller et kvaternært ammoniumsalt.
I J. Antibiotics, Vol. XXIV, s. 923-927 (Egger et al.) er der be-10 skrevet antimikrobielle pleromutilinderivater med en svovlholdig sidekæde, som bl.a. bærer mættede heterocycliske grupper, der via et heteroatom og via en bro med mindst 2 carbonatomer er knyttet til 3
DK 155669B
svovlatomet i sidekæden. Der er i det pågældende litteratursted ingen angivelse af forbindelser, der fremstilles ved fremgangsmåden ifølge den foreliggende opfindelse.
Fremgangsmåden udføres hensigtsmæssigt i nærværelse af et alkali-5 metal-lavere alkoxid, f.eks. natriumethoxid eller -methoxid. Dette fremstilles fortrinsvis in situ. Forbindelsen med formlen III kan bekvemt opløses i en opløsning af natrium i en vandfri lavere alkanol, f.eks. methanol eller ethanol. En opløsning af forbindelsen med formlen II i et inert organisk opløsningsmiddel, f.eks. en aliphatisk keton 10 såsom methylethylketon eller acetone, tilsættes bekvemt derefter.
Fremgangsmåden udføres hensigtsmæssigt ved en temperatur, der ligger mellem stuetemperatur og reaktionsblandingens tilbagesvalingstemperatur, især mellem 22 og 55°C. Reaktionstiden kan typisk ligge mellem 2 og 12 timer.
15 De resulterende forbindelser med formlen I kan isoleres og renses på sædvanlig måde. Om ønsket kan den fremstillede forbindelse med formlen I omdannes til syreadditionssaltformer og kvaternære ammoniumsaltformer på sædvanlig måde.
Et særlig foretrukket aspekt af opfindelsen går ud på, at der frem-20 stilles 19,20-dihydro-14-O-[(3-amino-1,2,4-triazol-5-yl)thioacetyl]mu- tilin eller et syreadditionssalt eller kvaternært ammoniumsalt deraf.
Forbindelserne med formlen I er indiceret til anvendelse som kemote-rapeutiske midler, især som antimikrobielle midler, hvilket f.eks. ses ved deres inhiberende effekt mod forskellige bakteriestammer, f.eks.
25 Staphylococcos aureus, Staphylococcos epidermis, Streptococcus pyogenes, Streptococcus aranson, Streptococcus pneumoniae, Streptococcus faecelis, Streptococcus viridans, Corynebacterium pyogenes,
Sarcina lutea, Klebsiella pneumoniae og Haemophilus influenzae, in vitro i seriefortyndingstesten ved en koncentration på f.eks. 0,01 -30 25 vg/ml og ved in vivo tests i mus. Forbindelserne udviser endvide re inhiberende virkning mod forskellige mycoplasma, f.eks. Mycoplasma hominis, Mycoplasma arthritidis, Mycoplasma pneumoniae og Urea-plasma urealyticum og chlamydia, in vitro i seriefortyndingstesten i koncentrationer på f.eks. 0,008 - 2,5 yg/ml.
DK 155669 B
4 I sammenligning med de i J. Antibiotikum bind XXIX (side 923-927) beskrevne forbindelser udmærker de ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelser sig ved at have kraftigere virkning over for infektioner.
5 Testmetode:
Streptococcus pyrogenes - sepsis
Testen udføres på grupper hver bestående af 6 hunmus af stammen NMRI og med en vægt på 18-22 g. Hver gruppe mus inficeres ved intraperitoneal indgivelse af Streptococcus pyrogenes Δ68. Testforbin-10 delsen administreres derefter peroralt 1 time og 4 timer efter infektionen i 2 deldoser, så at der fås den ønskede totale mængde til terapi. Dyrene observeres dagligt i 10’ dage efter infektionen. En' kontrolgruppe inficeres, men behandles ikke, hvilket viser infektionens forløb. Den procentvise andel af overlevende og helbredte dyr i 15 hver gruppe beregnes, og hvis forbindelserne har været aktive nok, α beregnes en ED^q-værdi (dvs. den dosis, der er nødvendig, for at 50% af dyrene overlever).
Forsøget udføres med nedenstående forbindelser
DK 155669 B
5
Testforbindelser O-CO-CHn-S-R,
0 I 1 L
R, R2 Ref.
Fremgangsmåden ifølge (A) Ethyl opfindelsen " N eksempel Ί 5 ® Vinyl " Fremgangsmåden ifølge opfindelsen eksempel 2 , tru ^ ru J· Antibiot. XXIX, (1) Ethy 22 '—^ 3 s. 923-927, forbindelse nr. 33 10 viny-j - " - J. Antibiot. XXIX, s.923-927, forbindelse nr. 28 (iii) Vinyl ”iCH2^2"NC] J* Antibiot· XXIX' s.923-927, forbindelse nr. 23 15 Resultater: ÉD^Q-Vaerdien for forbindelse A = 47 mg/kg EDsQ-Vasrdien for forbindelse B = 80 mg/kg
DK 155669 B
6
For forbindelse (i) er aktiviteten ved den højste testede koncentration (100 mg/kg)
For forbindelse (ii) er højeste dosis ikke tilstrækkelig til bestemmelse af ED^Q-værdien 5 For forbindelse (iii) er ED^Q-værdien signifikant højere end 100 mg/kg.
Biologiske data MIC-Værdier (værdier for minimal inhiberende koncentration) mod Staphylococcus aureus i standardseriefortyndingstests for de ved 10 fremgangsmåden ifølge den foreliggende opfindelse var:
Forbindelse frem- ' MIC-Værdi stillet ifølge yg/ml eksempel nr.
15 1 0,062 2 0,031 3 0,031 4 0,156 5 0,078 20 6 0,5 7 0,625 8 1,25 9 0,125 10 0,0097 25 11 0,062 12 0,156 13 0,015
Forbindelserne viser også inhiberende virkning mod forskellige obli-30 gate anaerober, f.eks. Bacteroides fragilis, Bacteroides melanino-genicus, Sphaerophorus necrophorus og Clostridium perfringens, in vitro i seriefortyndingstesten ved koncentrationer på f.eks. 0,1-4
DK 155669 B
7 ug/ml og in vivo i mus ved en dosis på f.eks. 50 - 200 mg/kg legemsvægt af dyret, peroralt eller subcutant.
Forbindelserne er derfor indiceret til anvendelse som antimikrobielle midler, især som antibakterielt virksomme antibiotika og til behandling 5 af infektionssygdomme forårsaget af obligate anaerober.
Til de ovenfor nævnte anvendelser ligger en indiceret egnet daglig dosis på mellem ca. 1 og 3 g, hensigtsmæssigt administreret i deldoser fra 2 til 4 gange daglig eller som retardform.
Forbindelserne alene eller i blanding med en tetracyclin kan admini-10 streres oralt eller parenteralt.
Det har også vist sig, at blandinger af forbindelser med formlen I med en tetracyclin med R-faktor kodet tetracyclin resistens viser en synergistisk antibakteriel virkning mod resistente stammer af denne type. Dette ses f.eks. ved bestemmelse af den minimale inhiberende 15 koncentration af blandingen og de enkelte komponenter i seriefortyndingstesten og ved at evaluere resultaterne efter Lowe's metode (isoboldiagram), jfr. Die Antibiotika, bind 1, del 1, 65ff, 1962. Sædvanlige tetracycliner, f.eks. chlortetracyclin, oxy tetracyclin, demethyltetracyclin, tetracyclin-dioxycyclin, monocyclin, metacyclin og 20 rolitetracyclin, kan anvendes i sådanne blandinger. Mængden af forbindelsen med formlen I i sådanne blandinger ligger hensigtsmæssigt på 10 - 90%, fortrinsvis på 20 - 35%, især på 25%, medens mængden af tetracyclinen hensigtsmæssigt ligger på 90 - 10%, fortrinsvis 80 - 65%, især 75% (alle beregnet på vægtbasis).
25 Blandingerne er især indiceret til behandling af infektionssygdomme i gastrointestinalkanalen og andre lokale infektioner i dette organ.
Forbindelserne med formlen I kan, når de anvendes alene eller i blanding med en tetracyclin, anvendes i fri baseform eller i form af et kemoterapeutisk tolerabelt syreadditionssalt eller kvaternært ammoni-30 umsalt. Disse saltformer har samme grad af aktivitet som de frie baseformer.
Egnede syreadditionssaltformer omfatter hydrochloridet, hydrogen- fumaratet, fumaratet og naphthalen-1,5-sulfonatet.
DK 155669B
8
Forbindelserne (eller blandinger deraf med en tetracyclin) kan blandes med et kemoterapeutisk tolerabelt fortyndingsmiddel eller bærestof 5 og eventuelt andre sædvanlige excipienser til fremstilling af galeniske former.
Fremgangsmåden ifølge opfindelsen belyses nærmere i nedenstående eksempler:
Eksempel 1.
10 19,20-Dihydro-14-O-((3-amino-1,2,4-triazol-5-yl)thioacetyl)mutilin 2,3 g natrium optages i 500 ml absolut ethanol. Efter dannelse af natriumethoxidet sættes 11,6 g 3-amino-5-mercapto-1,2,4-triazol til opløsningen.
Blandingen lades reagere i 3 timer ved 25°C, hvorefter den blandes 15 med en opløsning af 53,5 g 19,20-dihydro-22-O-tosylpleuromutilin i 200 ml ethylmethylketon. Den homogene reaktionsblanding holdes i 12 timer ved 25°C og hældes derefter ud i vand og ekstraheres tre gange med 500 ml ethylacetat. Den rensede ethylacetatekstrakt rystes med vand, tørres over natriumsulfat og inddampes i vakuum. Råpro-20 duktet chromatograferes over silicagel (eluant: ethylacetat), hvorved der fås titelforbindelsen, smeltepunkt 213 - 215°C (Isopropanol/vand). NMR-Spektrum (dimethylsulfoxid): 5,76 (bred, 2H, Nh^), 5,52 (d, IH, H14, JH14H13 = 8 Hz), 3,76 (s, 2H, S-CH2-CO), 3,35 (m, 1H, H„).
25 IR-Spektrum (KBr): v „ =2600-3600 tbred), 1720, 1635, 1280 cm'1.
mex
De i de nedenstående eksempler angivne forbindelser kan fremstilles på analog måde som beskrevet i eksempel 1 under anvendelse af relevante udgangsmaterialer i omtrentlig ækvivalente mængder: 14-0- ((3-Amino-1,2,4-triazol-5-yl)thioacetyl)mutilin 9
DK 155669B
Eksempel 2.
NMR-Spektrum (CDCI3): 5,68 (d, 1H, H^, JH14H|3 = 8 Hz), 3,34
Cd, IH, Hn, JHnH10 = 6 Hz), 3,7 (s, 2H, S-CHj-CO), 5,26-4,95 5 (m, 4H, NH2 + 2H20), 6,5-6,16 (m, IH, Hig).
hR-Spektrum (KBr): v = 3300 (bred), 1720, 1625, 1575, 1270 rndx -1 cm .
Eksempel 3.
14-0-((4-Methylsulfonyl-5-amino-1,2,4-triazol-3-yl)thioacetyl)mutilin
10 NMR-Spektrum (CDCL): 5,9 (s, 2H, NH,), 5,76 (d, 1H, H
0 1 14' JH14H13 = 8 Hz)' 3,81 (s' 2H' s"CH2'coi' 3'3 (s' 3H' CH3S02-), 3,4 (m, 1H Hn).
IR-Spektrum (KBr): vmav = 3400 (bred), 1720, 1625, 1265, 1275, 1180 ΓΠαΧ cm- .
15 Eksempel 4.
14-0-((4-Amino-1,2,4-triazol-3-yl)thioacetyl)mutilin NMR-Spektrum (CDCI3): 8,26 (s, 1H, triazol-H), 5,7 (d, 1H, H^, JH14H13 = 8 Hz^' 5'08 (s, 2H,NH2), AB-system (v^ = 3,86, νβ=3,75, JAB=16,2 Hz, S-CH2-0), 3,34 (dd, 1H, Hn, J=6,3 Hz, J=10,2 Hz).
20 IR-Spektrum (KBr): vmgx = 3400 (bred), 1720 cm
DK 155669B
Eksempel 5.
14-0-((3-(4-Pyridyl)-1,2,4-triazol-5-yl)thioacetyl)mutilin-hydrochlorid ίο NMR-Spektrum (dimethylsulfoxid): 8,95 (d, 2H, pyridin-H, J=6,3 Hz), 8,36 (d, 2H-pyridin-H, J=6,3 Hz), 5,55 (d, IH, H^, JH14H13 = 5 8 Hz), 4,16 (s, 2H, S-CH2-CO), 3,4 (d, 1H, H^, JH-jgH.,., = 6,3
Hz).
IR-Spektrum (KBr): v__v = 3600-2500 (bred), 1725, 1635 cm Eksempel 6.
14-0-((4-Amino-3-trifluormethyl-1,2,4-triazol-5-yl)thioacetyl)mutilin 10 NMR-Spektrum (CDCI3): 5,74 (d, IH, H^, JHMH13 = 8 Hz), 5,18 (s, 2H, NH2), 3,9 (s, 2H, S-CH2CO), 3,38 (m, IH, H^).
IR-Spektrum (KBr): v = 3400 (bred), 1720, 1190, 1150 cm ^.
max
Eksempel 7.
14-0-((4-Amino-3-methyl-1,2,4-triazol-5-yl)thioacetyl)mutilin 15 NMR-Spektrum (CDCIg): 5,72 (d, IH, H14, JH14H13 = 8 Hz), 4,97 (s, 2H, NH2), AB-system (v^=3,84, Vg=3,69, J^g=16,2 Hz, S-CH2-CO), 3,38 (dd, H^, J=6,3 Hz, J=10,2 Hz).
IR-Spektrum (KBr): v = 3400 (bred), 1725 cm \ max
Eksempel 8.
20 14-0-((3-Methyl-4-acetamido-1,2,4-triazol-5-yl)thioacetyl)mutilin NMR-Spektrum (CDCI3): 5,7 (d, IH, H^, JH14H13 = 8 Hz), 3,8 (s, 2H, S-CH2-CO), 3,38 (m, IH, Hn), 2,33 (s, 3H, CH3CO-N), 2,26 (s, 3H, triazol-CHg).
IR-Spektrum (KBr): v = 3400 (bred), 1720, 750 cm max 14-0-((3-(Methoxysulfonylethylca rboxamido)-1,2,4-triazol-5-yl)thio- acetyDmutilin 11
DK 155669B
Eksempel 9.
NMR-Spektrum (CDCIg): 5,72 (d, 1H, Hu, JH14H13 = 8 Hz), 3,82 5 (s, 2H, S-CH2-CO), 3,34 (m, 1H, H^), 3,14 (s, 3H, -0-CH3).
IR-Spektrum (KBr): v = 3400 (bred), 1720, 1625, 1550, 1305, max 1110, 730 cm-1.
Eksempel 10.
14-0-((1-Ethylaminocarbony!-3-amino-1,2,4-triazoI-5-yl)thioacety1)-10 mutilin NMR-Spektrum (CDCI3/CD3OD 10:1): 5,74 (d, IH, Hj4, JHMH13 = 8 Hz), 3,75 (s, 2H, S-CH2-CO), 3,38 (q, 2H, CHg-O^-N), 3,4 (m, 1H, Hn), 1,26 (t, 3H, CH3-CH2-N).
IR-Spektrum (KBr): v =3540, 3430, 3310, 1710, 1630, 1300 cm max 15 Smeltepunkt: 230 - 232°C.
Eksempel 11.
14-0-((3-Amino-4-formyl-1,2,4-triazol-5-yI)thioacetyl)mutilin NMR-Spektrum (CDCIg): 8,52 (s, 1H, formyl-H), 5,74 (d, IH, H^4, JH14H13 = 8 Hz)' 3,82 (s' 2H' s_CH2C0)' 3'36 ΊΗ' Hn)· 20 IR-Spektrum (KBr): v = 3600-2800 (bred), 1725, 1585, 1290 cm ^ max
Eksempel 12.
12
DK 155669 B
14-0-((3-Amino-l- (carbethoxythiocarbamyl)-1,2,4-triazol-5-yl)thioace-tyl)mutilin NMR-Spektrum (CDCI3): 7,74 (b, 2H, NH2), 5,81 (d, IH, H^, 5 JH14H13 = 8 Hz), 4,37 (q, 2H, O-CHJZHJ, 3,83 (s, 2H, S-CH2-C0), 3,4 (d, IH, H^, JH11H1() = 6,3 Hz), 1,38 (t, 3H, 0-CH2CH3).
IR-Spektrum (KBr): vmav = 3300 (bred), 1770, 1725, 1635, 1465, 1185
moX
-1 cm .
10 Eksempel 13.
14-0-((3-Amino-4-(ethylaminothiocarbonyl)-1,2,4-triazol-5-yl)thioace- tyl)mutilin NMR-Spektrum (CDCI3): 8,56 (m, IH, NH), 7,4 (b, 2H, NH2), 5,76 (d, IH, H14, JHhH13 = 8 Hz), 3,78 (s, 2H, S-CH2-CO), 3,68 (m, 15 2H, N-CH2-CH3), 3,38 (dd, 1H, H^, J=6,3 Hz, J=10,2 Hz), 1,33 (t, 3H, N-CH2-CH3).
IR-Spektrum (KBr): v = 3340 (bred), 1720, 1630, 1290 cm
ΓΠα X
Eksempel 14.
14-0-((4-Bls-(methylsulfonylamino)-1,2,4-triazol-3-yl)thioacetyl)mutilin 20 NMR-Spektrum (CDCI3): 8,28 (s, 1H, triazol-H), 5,72 (d, IH, H14, ^14^13 = δ Hz^' AB-system (v^=4,18, νβ=4,02, JAB = 16,2 Hz, S-CH2-CO), 3,6 (s, 3H, CHgSOj-), 3,58 (s, 3H, CHgSO^), 3,34 (m, IH, Hn).
IR-Spektrum (KBr): v = 3450 (bred), 1720, 1380, 1160 cm \ ΓΠαΧ

Claims (2)

14-0-((3-(2-Pyridyl)-1,2,4-triazol-5-yl)thioacetyl)mutilin. DK 155669B Eksempel 15. NMR-Spektrum (CDCIg): 8,82 (d, IH, pyridin-H, J=5 Hz), 8,24 (d, IH, pyridin-H, J=10 Hz), 7,9 (m, IH, pyridin-H), 7,45 (m, 1H, 5 pyridin-H), 5,78 (d, 1H, H.^, JH^H^ = 8 Hz), 4,0 (s, 2H, S-CH2-CO), 3,4 (m, IH, H^). IR-Spektrum (KBr): v = 3500-2800 (bred), 1720, 1450, 1280 cm-1. ΓΠ3Χ UV-Spektrum (CHgOH): 232 nm (ε = 12.400), 282 (8170). Patentkrav.
1. Analogifremgangsmåde til fremstilling af forbindelser med den almene formel I N-N OCOCH2s4 Jl— Y o CK3 i 04^4-·ι CHj OH hvor R betegner ethyl eller vinyl; Y betegner hydrogen, amino, trifluormethyl, C-j^-alkyl, pyridyl eller 15 - N (R3)(R4); DK 155669B 3 4 Z betegner hydrogen, ^-alkylsulfonyl, amino, formyl, -N(RJ)(R^), -S(CH2)nN(R3)(R4) eller CX.NHR6; 3 4 R og R har samme eller forskellig betydning, og hver betegner hydrogen, C-j^-alkanoyl, der eventuelt er substitueret med alkoxysulfo-5 nyl; _^-alkylsulfonyl eller C-j^-alkyl; 0 R betegner C^^-alkyl eller C^-alkoxycarbonyl; n betegner 2-5; og X betegner oxygen eller svovl, eller syreadditionssalte eller kvaternære ammoniumsalte deraf, 10 kendetegnet ved, at en forbindelse med den almene formel II ococh2r5 Λ CH- 1 O 3 /V π >—Λ ch3 oh 1 5 hvor R har den ovenfor anførte betydning, og R betegner chlor, brom eller -OSC^R^/ hvor R^ betegner alkyl eller aryl, omsættes med 15 en forbindelse med den almene formel III HS J L· « z DK 155669 B hvor Y 09 Z har den ovenfor anførte betydning, og en vunden forbindelse med formlen I, om ønsket, omdannes til et syreadditionssalt eller et kvaternært ammoniumsalt.
2. Fremgangsmåde ifølge krav 1, 5 kendetegnet ved, at der fremstilles 19,20-dihydro-14-O-[(3-amino-1,2,4-triazol-5-yl)thioacetyl]mutilin eller et syreadditionssalt eller kvaternært ammoniumsalt deraf.
DK004280A 1979-01-12 1980-01-03 Analogifremgangsmaade til fremstilling af pleuromutilinderivater DK155669C (da)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH30979 1979-01-12
CH30979 1979-01-12
CH727479 1979-08-08
CH727479 1979-08-08

Publications (3)

Publication Number Publication Date
DK4280A DK4280A (da) 1980-07-13
DK155669B true DK155669B (da) 1989-05-01
DK155669C DK155669C (da) 1989-09-25

Family

ID=25684188

Family Applications (1)

Application Number Title Priority Date Filing Date
DK004280A DK155669C (da) 1979-01-12 1980-01-03 Analogifremgangsmaade til fremstilling af pleuromutilinderivater

Country Status (17)

Country Link
US (1) US4428953A (da)
EP (1) EP0013768B1 (da)
AU (1) AU533691B2 (da)
CA (1) CA1125778A (da)
CY (1) CY1353A (da)
DE (1) DE2966635D1 (da)
DK (1) DK155669C (da)
ES (1) ES8101536A1 (da)
FI (1) FI65994C (da)
HK (1) HK40587A (da)
IE (1) IE49356B1 (da)
IL (1) IL59108A (da)
MY (1) MY8700726A (da)
NZ (1) NZ192576A (da)
PH (1) PH17391A (da)
PT (1) PT70682A (da)
YU (1) YU42658B (da)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT400674B (de) * 1991-07-24 1996-02-26 Biochemie Gmbh Pharmazeutische pleuromutilin-zubereitung
AT397654B (de) * 1992-05-04 1994-06-27 Biochemie Gmbh Neue pleuromutilinderivate, ihre verwendung und verfahren zu ihrer herstellung
CZ212498A3 (cs) * 1996-01-03 1998-12-16 Smithkline Beecham P. L. C. Karbamoyloxyderiváty mutilinu, způsob výroby a farmaceutický prosředek
UY25225A1 (es) * 1997-10-29 2000-12-29 Smithkline Beecham Plc Derivados de pleuromutilina utiles como agentes antimicrobianos
GB9912657D0 (en) * 1999-06-01 1999-07-28 Smithkline Beecham Plc Novel compounds
GB9918037D0 (en) 1999-07-30 1999-09-29 Biochemie Gmbh Organic compounds
PE20020676A1 (es) 2000-09-13 2002-08-27 Biochemie Gmbh Compuestos de mutilina como antibacterianos
GB0207495D0 (en) * 2002-03-28 2002-05-08 Biochemie Gmbh Organic compounds
GB0308114D0 (en) * 2003-04-08 2003-05-14 Glaxo Group Ltd Novel compounds
ATE450535T1 (de) * 2003-09-03 2009-12-15 Glaxo Group Ltd Neues verfahren zur herstellung von pleuromutilinderivaten
GB0504314D0 (en) * 2005-03-02 2005-04-06 Glaxo Group Ltd Novel polymorph
US20080171766A1 (en) * 2005-03-10 2008-07-17 Smithkline Beecham Corporation Novel Method
EP1808431A1 (en) * 2006-01-16 2007-07-18 Nabriva Therapeutics Forschungs GmbH Mutilin derivatives and their use as pharmaceutical
US8222407B2 (en) * 2007-05-24 2012-07-17 Kyorin Pharmaceutical Co., Ltd. Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position
CN110437157B (zh) * 2019-07-05 2022-05-17 西华大学 一种芳基嘧啶类截短侧耳素衍生物及其制备方法和用途
CN110818648B (zh) * 2019-12-05 2021-03-16 华南农业大学 一种具有三氮唑侧链的截短侧耳素衍生物及其制备方法和应用
CN111253322A (zh) * 2020-03-12 2020-06-09 中国农业科学院兰州畜牧与兽药研究所 含有n-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用
CN111689914B (zh) * 2020-06-18 2021-09-24 华南农业大学 一种具有1,2,4-三唑席夫碱的截短侧耳素衍生物及制备与应用
CN114716384B (zh) * 2022-03-10 2023-09-26 中国农业科学院兰州畜牧与兽药研究所 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用
CN114736194A (zh) * 2022-03-29 2022-07-12 中牧实业股份有限公司 一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物及其制备方法与应用
CN117257794A (zh) * 2023-07-20 2023-12-22 华南农业大学 一种侧链含氮杂环或烷基胺的截短侧耳素衍生物在制备防治鸡毒支原体药物中的用途
CN116874472A (zh) * 2023-07-20 2023-10-13 华南农业大学 一种具有1，2，4-三氮唑侧链的截短侧耳素衍生物及其制备方法与应用
CN117069668A (zh) * 2023-08-09 2023-11-17 中国农业科学院兰州畜牧与兽药研究所 一种具有三嗪侧链的截短侧耳素类化合物及其制备方法和应用
CN117304133B (zh) * 2023-09-26 2026-03-17 华南农业大学 一种具有噻唑侧链的截短侧耳素衍生物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1312148A (en) * 1969-07-25 1973-04-04 Biochemie Gmbh Mutilin derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3979423A (en) 1969-07-25 1976-09-07 Biochemie Gesellschaft M.B.H. 14-Desoxy-14-tosyloxyacetoxy-mutilin
US3919290A (en) 1972-10-03 1975-11-11 Sandoz Ltd Substituted 14-desoxy-mutilins
US4160086A (en) 1974-04-27 1979-07-03 Beecham Group Limited 3-Heterocyclicthio-7-α-carboxy 2-aryl acetamido cephalosporanic acid
US4143166A (en) 1975-02-04 1979-03-06 Fujisawa Pharmaceutical Co., Ltd. 7[(2-Hydroxyamino-2-disubstituted phenyl-acetamido)-]3-heterocyclicthio-3-cephem-4-carboxylic acids
US4113943A (en) 1977-03-10 1978-09-12 E. R. Squibb & Sons, Inc. 7β-[(2-Amino-1,2-dioxoethyl)amino]acyl cephalosporins

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1312148A (en) * 1969-07-25 1973-04-04 Biochemie Gmbh Mutilin derivatives

Also Published As

Publication number Publication date
US4428953A (en) 1984-01-31
IE800046L (en) 1980-07-12
HK40587A (en) 1987-05-29
IE49356B1 (en) 1985-09-18
FI65994C (fi) 1984-08-10
IL59108A0 (en) 1980-05-30
FI65994B (fi) 1984-04-30
CA1125778A (en) 1982-06-15
ES487584A0 (es) 1981-02-16
NZ192576A (en) 1984-05-31
ES8101536A1 (es) 1981-02-16
DK155669C (da) 1989-09-25
EP0013768B1 (en) 1984-02-01
EP0013768A1 (en) 1980-08-06
IL59108A (en) 1983-07-31
CY1353A (en) 1987-04-24
AU533691B2 (en) 1983-12-08
PT70682A (en) 1980-02-01
DE2966635D1 (en) 1984-03-08
FI800024A7 (fi) 1980-07-13
YU6280A (en) 1983-02-28
MY8700726A (en) 1987-12-31
YU42658B (en) 1988-10-31
AU5453580A (en) 1980-07-17
PH17391A (en) 1984-08-08
DK4280A (da) 1980-07-13

Similar Documents

Publication Publication Date Title
DK155669B (da) Analogifremgangsmaade til fremstilling af pleuromutilinderivater
DE3881443T2 (de) Imidazol-Verbindung und diese enthaltende biozide Zusammensetzungen.
DE69425442T2 (de) 1,3,5- trisubstituierte pyrazolverbindungen zur behandlung von entzündungen
DE69434316T2 (de) Verfahren zur Herstellung von trisubstituierten Imidazolverbindungen mit mehreren therapeutischen Eigenschaften
DE3340967C2 (de) Aminderivate, Salze derselben, Verfahren zur Herstellung derselben sowie Anti-Ulcusmittel mit einem Gehalt derselben
RU2582338C2 (ru) Соединения пиразола в качестве ингибиторов сигма рецепторов
DE69914931T2 (de) 4,5-dehydroisoxazole derivate und ihre pharmazeutische verwendung
CZ300106B6 (cs) 6-O-substituované makrolidové slouceniny, zpusob jejich prípravy a jejich použití a farmaceutické kompozice je obsahující
PL105891B1 (pl) Sposob wytwarzania nowych pochodnych pirazoliny
DE3916430A1 (de) Verfahren zur herstellung von 3-amino-5-aminocarbonyl-1,2,4-triazol-derivaten
SU1162372A3 (ru) Способ получени производных замещенного имидазола или их гидрохлоридов
JPWO2009041447A1 (ja) ５員複素環化合物
JP2016505536A (ja) 駆虫性化合物及び組成物並びにこれらの使用方法
HU210904B (en) Process and composition for immunization of plants and process for the preparation of the new benzothiadiazole derivatives usable as active ingredients
DE3033169A1 (de) 3,4-disubstituierte 1,2,5-thiadiazol-1-oxide und -1,1-dioxide
AU2008252068A1 (en) Inhibition of Raf Kinase Using Substituted Heterocyclic Ureas
DE60001182T2 (de) Erythromycin-Derivate, ihr Verfahren zur Herstellung und ihre Verwendung als Arzneimittel
DE69915487T2 (de) Erythromycin-derivate mit antibiotischer wirkung
DE3889987T2 (de) N-[(2-Oxopyrrolidin-1-yl)acetyl]piperazin-Derivate und Arzneimittel gegen senile Dementia.
EP0124067A1 (de) 2-(Aminoalkyl)-pyrrol-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung
DE69618694T2 (de) N-Acetylpiperazinderivat, antibakteriell und anti-ulcer Medikament
NO138025B (no) Analogifremgangsm}te til fremstilling av antimykotisk virksomme 1-etyl-imidazoler
DE69015270T2 (de) Cyclische vinyloge N-hydroxy-N-methylharnstoffe verwendbar als 5-Lipoygenase-Inhibitoren.
EP0605493B1 (de) ANTIALLERGISCHE THIADIAZOLO(4,3-a)PYRIDINDERIVATIVE
DE3405632A1 (de) Neue pleuromutilinderivate, verfahren zu ihrer herstellung und ihre verwendung

Legal Events

Date Code Title Description
PBP Patent lapsed