NO168357B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DISULFIDES - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DISULFIDES Download PDF

Info

Publication number
NO168357B
NO168357B NO860908A NO860908A NO168357B NO 168357 B NO168357 B NO 168357B NO 860908 A NO860908 A NO 860908A NO 860908 A NO860908 A NO 860908A NO 168357 B NO168357 B NO 168357B
Authority
NO
Norway
Prior art keywords
het
substituted
compound
ppm
carboxy
Prior art date
Application number
NO860908A
Other languages
Norwegian (no)
Other versions
NO168357C (en
NO860908L (en
Inventor
Klaus Fleischmann
Walter Duerckheimer
Juergen Blumbach
Michael Limbert
Hans-Ulrich Schorlemmer
Gerhard Dickneite
Hans-Harald Sedlacek
Original Assignee
Hoechst 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 Hoechst Ag filed Critical Hoechst Ag
Publication of NO860908L publication Critical patent/NO860908L/en
Publication of NO168357B publication Critical patent/NO168357B/en
Publication of NO168357C publication Critical patent/NO168357C/en

Links

Classifications

    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • 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
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines 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
    • 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
    • C07D277/36—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
    • C07D277/02—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
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • 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
    • C07D285/12—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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

Foreliggende oppfinnelse vedrører analogifremgangsmåte for fremstilling av terapeutisk aktive disulfider. Det er kjent at en levende organismes forsvarsmekanismer som kort betegnes som humoral immunitet og cellulær immunitet virker sammen for å nøytralisere og å eliminere fremmedstoffer som frembringer patogenetiske endringer, og som kan være skadelige, spesielt mikroorganismer eller neoplastiske celler. The present invention relates to an analogue method for the production of therapeutically active disulphides. It is known that a living organism's defense mechanisms, briefly referred to as humoral immunity and cellular immunity, work together to neutralize and eliminate foreign substances that produce pathogenetic changes and that may be harmful, especially microorganisms or neoplastic cells.

Immunologiske undersøkelser viste at det er en sammenheng mellom den ved indre og ved ytre faktorer provoserte nedgang av den immunologiske aktivitet, og økningen av infeksjons-eller tumorsykdommer. Dertil oppstår andre sykdommer ved endringer av immunsystemets funksjoner. Hertil hører eksempelvis autoimmunsykdommer, eller ved immunkomplekse frem-bragte sykdommer. Man har derfor lenge søkt etter immunstimulanter, dvs. etter stoffer som er i stand til å endre mottagerens immunologiske aktivitet, fortrinnsvis å øke og som på grunn av deres høye virkning og gode holdbarhet, muliggjør en bred anvendelse til understøttelse av legemets motstandskrefter. Eksempler som ble undersøkt men hensyn til stimulering av immuniteten, er BCG og C. Parvum, videre ekstrakten av M. tuberculoser og Bruceller. Immunological investigations showed that there is a connection between the decrease in immunological activity provoked by internal and external factors, and the increase in infectious or tumor diseases. In addition, other diseases arise from changes in the functions of the immune system. This includes, for example, autoimmune diseases, or diseases caused by immune complexes. People have therefore long searched for immunostimulants, i.e. for substances which are able to change the recipient's immunological activity, preferably to increase it and which, due to their high effect and good durability, enable a wide application to support the body's resistance forces. Examples that were investigated but with regard to stimulation of immunity are BCG and C. Parvum, further the extract of M. tuberculosis and Brucella.

Disse stoffer frembringer imidlertid i de konsentrasjoner som de kommer til anvendelse tydelige bivirkninger, som f.eks. i forskjellig grad lokale granulomer. Manglende kjennskap til den nøyaktige natur av stoffene vanskeliggjør en systematisk undersøkelse med god reproduserbarhet av de kliniske resultater. Ønskelig er således i denne forbindelse nye immunstimulanter, som er kjemisk definerte stoffer og har liten toksisitet, som f.eks. Bestatin, som for tiden er et intenst undersøkt lavmolekylært iramunstimulans, og generelt er et vitenskapelig referansestoff. However, in the concentrations in which they are used, these substances produce clear side effects, such as e.g. to varying degrees local granulomas. Lack of knowledge of the exact nature of the substances makes a systematic investigation with good reproducibility of the clinical results difficult. New immunostimulants, which are chemically defined substances and have little toxicity, such as e.g. Bestatin, which is currently an intensively researched low-molecular-weight iramun stimulant, is generally a scientific reference substance.

Overraskende ble det nå funnet at forbindelsene har en høy immunstimulerende og iromunrestaurativ virkning, slik de eksempelvis uttrykker i DTH-reaksjonen på fårerytrocytter, i 2 Surprisingly, it was now found that the compounds have a high immunostimulating and immunorestorative effect, as they for example express in the DTH reaction on sheep erythrocytes, in 2

aktivering av mononukleære fagocytter og i en utpreget CSF-aktivitet. Disse immunstimulerende effekter kunne eksempelvis også iakttas i en økning av motstandskraften mot infeksjoner. Dessuten har forbindelsene overraskende cytostatisk virkning, således eksempelvis mot B16-melanomet på mus. activation of mononuclear phagocytes and in a pronounced CSF activity. These immune-stimulating effects could, for example, also be observed in an increase in resistance to infections. In addition, the compounds have a surprising cytostatic effect, for example against the B16 melanoma in mice.

Foreliggende oppfinnelse vedrører analogifremgangsmåte for fremstilling av terapeutisk aktive disulfider for immunstimulasjon, immunrestaurasjon og cytostatisk behandling med den generelle formel The present invention relates to an analogous method for the production of therapeutically active disulfides for immune stimulation, immune restoration and cytostatic treatment with the general formula

hvori in which

Het' betyr 1,3-tiazolyl, som er substituert med C^Cg-alkyl, Het' means 1,3-thiazolyl, which is substituted by C 1 -C 8 -alkyl,

karboksy-C1-C6-alkyl, karboksy eller C2-C5-acylamino, idet acyl er resten av en alifatisk dikarboksylsyre; eller 1,2,4-triazolyl, som er substituert med hydroksy og fenyl; carboxy-C1-C6-alkyl, carboxy or C2-C5-acylamino, acyl being the residue of an aliphatic dicarboxylic acid; or 1,2,4-triazolyl, which is substituted with hydroxy and phenyl;

eller or

l,3,4-tiadiazolyl, som er substituert med karboksy C^- C^-alkyltio; eller 1,3,4-thiadiazolyl, which is substituted with carboxy C 1 -C 4 -alkylthio; or

dihydro-1,2,4-triazinyl, som er substituert med C^-Cg-alkyl, halogeno-C2-C4-alkenyl, okso eller hydroksy eller dihydro-1,2,4-triazinyl, which is substituted by C 1 -C 8 -alkyl, halogeno-C 2 -C 4 -alkenyl, oxo or hydroxy or

benzimidazolyl, som er substituert med karboksy; idet Het' er substituert med minst en direkte eller til en substituent-bundet karboksygruppe eller en direktebundet hydroksygruppe, idet disse begge gruppene kan foreligge i form av et fysiologisk tålbart salt, kjennetegnet ved at benzimidazolyl, which is substituted with carboxy; in that Het' is substituted by at least one directly or to a substituent-bonded carboxy group or a directly bonded hydroxy group, both of these groups can be present in the form of a physiologically tolerable salt, characterized in that

a) en forbindelse med formel II a) a compound of formula II

hvor Het' som har ovennevnte betydning, ved omsetning med et where Het' which has the above meaning, when traded with a

; oksydasjonsmiddel overføres til en forbindelse med formel I' ; oxidizing agent is transferred to a compound of formula I'

eller or

b) en forbindelse med formel III b) a compound of formula III

hvori Het' har ovennevnte betydning, og X betyr en reaktiv wherein Het' has the above meaning, and X means a reactive

lett avspaltbar gruppe, omsettes med Me2S2, idet Me betyr et alkalimetall eller easily cleavable group, is reacted with Me2S2, Me meaning an alkali metal or

c) en forbindelse med formel IV c) a compound of formula IV

hvori Het<1> og Me har ovennevnte betydning, omsettes med jod i in which Het<1> and Me have the above meaning, is reacted with iodine i

vandig medium. aqueous medium.

Disse forbindelsene utgjør en klasse immunfarmakologisk og cytostatisk virksomme stoffer som er kjemisk definerte, har liten toksisitet og som sådanne eller i kombinasjon med andre virksomme stoffer er verdifulle legemidler. Forbindelsene har en LD5Q-verdi på mer enn 1000 mg/kg ved intravenøs injeksjon på mus. Den virksomme immunmodulatoriske og cytostatiske mengde ligger hos varmblodspattedyr i området fra 0,5 til 100 mg/kg legemsvekt pr. parenteral eller oral inngivning uten derved å vise toksiske bivirkninger, og er dermed meget godt egnet for behandling av sykdommer av immunsystemet. These compounds form a class of immunopharmacologically and cytostatically active substances which are chemically defined, have little toxicity and as such or in combination with other active substances are valuable medicines. The compounds have an LD5Q value of more than 1000 mg/kg when injected intravenously into mice. The effective immunomodulatory and cytostatic amount in warm-blooded mammals is in the range from 0.5 to 100 mg/kg body weight per parenteral or oral administration without thereby showing toxic side effects, and is thus very well suited for the treatment of diseases of the immune system.

For Het skal det eksempelvis nevnes følgende grunnleggende ringsystemer: Tiazoly, triazolyl, tiadiazolyl og benzimidazolyl, idet ringsystemene også helt eller delvis kan være hydrogenert, som f.eks. dihydrotriazinyl. For Het, for example, the following basic ring systems should be mentioned: Thiazoly, triazolyl, thiadiazolyl and benzimidazolyl, as the ring systems can also be fully or partially hydrogenated, such as e.g. dihydrotriazinyl.

Foretrukket er 5-leddede ringsystemer med et svovelatom og 1 til 2 nitrogenatomer, som tiazolyl. Foretrukket er videre 5-leddede ringsystemer med 2 eller 3 nitrogenatomer, som f.eks. triazolyl, fortrinnsvis 1,2,4-triazolyl, Preferred are 5-membered ring systems with a sulfur atom and 1 to 2 nitrogen atoms, such as thiazolyl. Further preferred are 5-membered ring systems with 2 or 3 nitrogen atoms, such as e.g. triazolyl, preferably 1,2,4-triazolyl,

Resten Het kan være substituert idet det kommer i betraktning eksempelvis følgende substituenter: Rettlinjede og forgrenede alkylgrupper med l til 6, fortrinnsvis 1-3 C-atomer, som f.eks. metyl, etyl, n- eller i-propyl, n- eller tert.-butyl, fortrinnsvis metyl. The residue Het can be substituted, considering for example the following substituents: Straight and branched alkyl groups with 1 to 6, preferably 1-3 C atoms, such as e.g. methyl, ethyl, n- or i-propyl, n- or tert-butyl, preferably methyl.

Foretrukket er heterocykelen Het<1>, som i den heterocykliske eller påkondenserte karbocykliske ring har en . eller to substituenter. Spesielt foretrukket er slike hvor av disse substituenter minst en har en sur gruppe spesielt en karboksygruppe, som eksempelvis karboksyalkyl eller karboksy-alkyltio. Preferred is the heterocycle Het<1>, which in the heterocyclic or condensed carbocyclic ring has a . or two substituents. Particularly preferred are those where at least one of these substituents has an acidic group, especially a carboxy group, such as, for example, carboxyalkyl or carboxyalkylthio.

Er substituenten ved heterocykelen Het' som f.eks. alkyl, alkenyl eller alkyltio, dessuten videresubstituert på overnevnte måte, så kan de også ha mer enn en substituent. Foretrukket er imidlertid deres enkle substitusjon. Is the substituent at the heterocycle Het' as e.g. alkyl, alkenyl or alkylthio, furthermore further substituted in the above-mentioned manner, they can also have more than one substituent. However, their simple substitution is preferred.

Såvidt forbindelsene med formel I<1> har sure funksjoner, kan de også foreligge i form av deres fysiologisk tålbare salter, eksempelvis som alkali- og jordalkalisalter. Insofar as the compounds of formula I<1> have acidic functions, they can also exist in the form of their physiologically tolerable salts, for example as alkali and alkaline earth salts.

En forbindelse med formel II overføres som nevnt til en forbindelse med formel I' ved omsetning med et oksydasjonsmiddel. Som oksydasjonsmidler skal det eksempelvis nevnes oksygen, hydrogenperoksyd, og under tiden under tilsetning av jernsalter som eksempelvis Mohr-salt eller under tilsetning av baser som eksempelvis natriumhydroksy, kaliumhydroksyd, natriumhydrogenkarbonat eller kaliumhydrogenkarbonat, organiske persyrer, som eksempelvis pereddiksyre, perbenzosyre, eller m-klorbenzosyre, elementær brom eller brom, og under tiden under tilsetning av baser, som eksempelvis natriumhydroksy eller kaliumhydroksy, FeCl3 eller K3 (Fe(CN)6). A compound of formula II is transferred, as mentioned, to a compound of formula I' by reaction with an oxidizing agent. Oxidizing agents include, for example, oxygen, hydrogen peroxide, and during the addition of iron salts such as Mohr's salt or during the addition of bases such as sodium hydroxy, potassium hydroxide, sodium hydrogen carbonate or potassium hydrogen carbonate, organic peracids, such as peracetic acid, perbenzoic acid, or m-chlorobenzoic acid , elemental bromine or bromine, and during the addition of bases, such as for example sodium hydroxy or potassium hydroxy, FeCl3 or K3 (Fe(CN)6).

Som oksydasjonsmiddel skal det som foretrukket nevnes oksygen, hydrogenperoksyd, organiske persyrer, som eksempelvis pereddiksyre, perbenzosyre, og m-klor-perbenzosyre og elementært jod. Oksydasjonen gjennomføres fortrinnsvis i vann eller et organisk oppløsningsmiddel, som eksempelvis metanol, etanol, iso-propanol, eddikestere med halogenerte hydro-karboner, som eksempelvis diklormetan og kloroform. Det kan også anvendes en blanding av disse oppløsningsmidler. Ved arbeider med oksygen, hydrogenperoksyd og persyrer er det å unngå anvendelse av oppløsningsmidler som som kjent kan danne eksplosive peroksyder, som eksempelvis eter, tetrahydrofuran, dioksan, aceton, metyletylketon, isopropanol, osv. Oxygen, hydrogen peroxide, organic peracids, such as, for example, peracetic acid, perbenzoic acid, and m-chloro-perbenzoic acid and elemental iodine should preferably be mentioned as oxidizing agents. The oxidation is preferably carried out in water or an organic solvent, such as methanol, ethanol, isopropanol, acetic esters with halogenated hydrocarbons, such as dichloromethane and chloroform. A mixture of these solvents can also be used. When working with oxygen, hydrogen peroxide and peracids, avoid the use of solvents which are known to form explosive peroxides, such as ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, isopropanol, etc.

Forbindelsene kan også fremstilles idet en forbindelse med formel III The compounds can also be prepared as a compound of formula III

hvor Het' har den ovenfor angitte betydning, og X betyr en reaktiv avspaltbar gruppe som halogen, fortrinnsvis klor eller brom, som -OS02R, idet R har betydningen av fortrinnsvis metyl, triklormetyl, fenyl, tolyl eller naftyl, som -OPO(OR'2), idet R' har betydningen av fortrinnsvis fenyl, omsettes med Me2S2, idet Me betyr et alkalimetall, fortrinnsvis natrium, og eventuelt overføres de overnevnte substituenter av Het' til andre av de ovenfor nevnte substituenter av Het'. where Het' has the meaning given above, and X means a reactive cleavable group such as halogen, preferably chlorine or bromine, such as -OS02R, where R has the meaning of preferably methyl, trichloromethyl, phenyl, tolyl or naphthyl, such as -OPO(OR' 2), where R' has the meaning of preferably phenyl, is reacted with Me2S2, where Me means an alkali metal, preferably sodium, and optionally the above-mentioned substituents of Het' are transferred to other of the above-mentioned substituents of Het'.

Videre kan forbindelsen fremstilles idet en forbindelse med formel IV hvori Het' og Me har overnevnte betydning, omsettes med jod i vandig medium, og eventuelt overføres de overnevnte substituenter av Het' til andre av de overnevnte substituenter av Het'. Furthermore, the compound can be prepared by reacting a compound of formula IV in which Het' and Me have the above-mentioned meaning with iodine in an aqueous medium, and possibly transferring the above-mentioned substituents of Het' to other of the above-mentioned substituents of Het'.

Omsetningen kan gjennomføres i et temperaturområde mellom ca. -40 *C og oppløsningsmidlets resp. oppløsningsmiddelbland-ingens kokepunkt, fortrinnsvis mellom ca. -10°C og ca. +40"C. The turnover can be carried out in a temperature range between approx. -40 *C and the solvent's resp. The boiling point of the solvent mixture, preferably between approx. -10°C and approx. +40"C.

Det er helt generelt mulig i disulfidene med formel I' i heterocyklisk Het' inneholdende substituenter å overføre til litteraturkjente fremgangsmåter til andre substituenter. Således kan eksempelvis en alkoksykarbonyl- eller amino-karbonylgruppe ved forsåpning eller i tilfelle aminokarbonyl-gruppen også ved nitrosering omdannes til den frie karboksyl-gruppe. It is quite generally possible in the disulfides of formula I' in heterocyclic Het' containing substituents to transfer to methods known in the literature to other substituents. Thus, for example, an alkoxycarbonyl or aminocarbonyl group can be converted to the free carboxyl group by saponification or, in the case of the aminocarbonyl group, also by nitrosation.

Det virksomme stoff kan administreres alene eller imidlertid også kombineres med et eller flere fortrinnsvis et annet legemiddel, som gunstig påvirker infeksjoner som eksempelvis frembringes ved bakterier, sopp eller vira og tumorsykdommer. De virksomme stoffer kan administreres parenteralt som også oralt. For den parenterale administrering kommer det i betraktning oppløsninger eller suspensjoner av det virksomme stoff i en farmasøytisk tålbar vektor, fortrinnsvis plante-olje, f.eks. jordnøttolje eller sesamolje, samt alkoholiske oppløsninger av det virksomme stoff, f.eks. etanol, propan-diol eller glycerol, eller i blandinger av de overnevnte oppløsningsmidler. For fremstilling av vandige oppløsninger, anvendes det virksomme stoff, fortrinnsvis i form av vannopp-løselige, fysiologisk tålbare salter. Tilberedningene kan inneholde de vanlige hjelpe- og bærestoffer. Som sådanne kommer det eksempelvis på tale fyllstoffer, emulgatorer, glide- og bufferstoffer, og smakskorrigerende stoffer. The active substance can be administered alone or, however, can also be combined with one or more preferably another drug, which favorably affects infections caused, for example, by bacteria, fungi or viruses and tumor diseases. The active substances can be administered parenterally as well as orally. For the parenteral administration, solutions or suspensions of the active substance in a pharmaceutically acceptable vector, preferably plant oil, e.g. peanut oil or sesame oil, as well as alcoholic solutions of the active substance, e.g. ethanol, propane-diol or glycerol, or in mixtures of the above-mentioned solvents. For the production of aqueous solutions, the active substance is used, preferably in the form of water-soluble, physiologically tolerable salts. The preparations may contain the usual auxiliary and carrier substances. As such, these include, for example, fillers, emulsifiers, slip and buffer substances, and taste correcting substances.

I det følgende forklares eksempelvis innvirkningen av forbindelsene på immunsvaret hos mus og deres immunstimulerende aktiviteter i forskjellige in vivo standard-metoder. De anvendte forskjellige prøvemetoder er som kjent spesielt godt egnet for vurdering av immunstimulanter og deres virkekvalitet. In the following, for example, the impact of the compounds on the immune response in mice and their immunostimulating activities in different in vivo standard methods is explained. As is known, the different test methods used are particularly well suited for assessing immunostimulants and their quality of action.

Eksperiment 1 Experiment 1

Virkning på den cellulære immunologiske reaksjon av forsinket type mot fåreerytrocytter (delayed type hypersensitivity, DTin . Effect on the cellular immunological reaction of delayed type against sheep erythrocytes (delayed type hypersensitivity, DTin.

Det ble administrert grupper på 5 hunn-NMRI-mus med en vekt på 18-20 g intravenøs enten IO<6> eller IO<9> røde blodlegemer fra får pr. dyr. Fåreerytrocytter gjelder i immunologien som standard-prøvestoff (antigen) til utløsning av cellulære og humorale immunreaksjoner, spesielt i denne prøveopplysning om funksjonsevnen av den T-celleavhengige komponent (T-hjelpe-cellene) av immunsystemet. Det ifølge utførelseseksempel 8 oppnådde prøvestoff (bis-(5-karboksymetyl-4-metyl-tiazol-2-yl)-disulfid) ble applisert intraperitonealt på dagene -3, -2, -1 og 0 i konsentrasjoner 20 mg/kg, 30 mg/kg og 40 mg/kg i fysiologisk kokesaltoppløsning. Etter 5 dager ble det på alle dyr injisert resp. 2 x IO<8> fåreerytrocytter i fotsålen, og 24 timer senere ble fotens hevelse målt. Fothevningen utløses ved en hudreaksjon av forsinket type, (delayed type hypersensitivity, DTH) og er som kjent for fagfolk et mål for det cellulære immunsvar. (Collins, F.M. og Mackaness G.B. , J. Immunol. 101, 830-845, 1968). I tabell 1 oppstilte resultater viser at det ved utlevering av stoffet dannet ifølge oppfinnelsen eksempelvis etter immunisering med IO<6 >fåreerytrocytter kommer til økning av det cellulære immunsvar. Et maksimum av stimulering kan denne eksperiment-blanding oppnå ved inngivning av 30 mg/kg prøvestoff. Groups of 5 female NMRI mice with a weight of 18-20 g were administered intravenously either IO<6> or IO<9> red blood cells from sheep per animals. Sheep erythrocytes apply in immunology as a standard test substance (antigen) for triggering cellular and humoral immune reactions, especially in this test information on the functionality of the T-cell-dependent component (T-helper cells) of the immune system. The test substance obtained according to embodiment 8 (bis-(5-carboxymethyl-4-methyl-thiazol-2-yl)-disulfide) was applied intraperitoneally on days -3, -2, -1 and 0 in concentrations 20 mg/kg, 30 mg/kg and 40 mg/kg in physiological saline solution. After 5 days, all animals were injected resp. 2 x 10<8> sheep erythrocytes in the sole of the foot, and 24 hours later the swelling of the foot was measured. The raised foot is triggered by a skin reaction of a delayed type (delayed type hypersensitivity, DTH) and, as is known to professionals, is a measure of the cellular immune response. (Collins, F.M. and Mackaness, G.B., J. Immunol. 101, 830-845, 1968). The results listed in Table 1 show that when the substance formed according to the invention is dispensed, for example after immunization with 10<6> sheep erythrocytes, there is an increase in the cellular immune response. A maximum of stimulation can be achieved with this experimental mixture by administering 30 mg/kg test substance.

Tabell 1 Table 1

Immunisering av mus med fåreerytrocytter-virkning på det cellulære immunsvar (DTH-reaksjon). Immunization of mice with sheep erythrocytes-effect on the cellular immune response (DTH reaction).

Eksperiment 2 Experiment 2

Innvirkning på stimuleringen av den uspesifikke immunitets-aktiverina av mononukleære faaocytter. Effect on the stimulation of the non-specific immunity activator by mononuclear phagocytes.

Her ble det undersøkt innvirkningen av det ifølge utførelses-eksempler 8 oppnådde prøvestoff, på stimuleringen av peri-tonealt makrofager ved 6-8 uker gamle NMRI-mus. Hunnmus fikk på parenteral eller oral måte prøvestoffet i en dose på 25 mg/kg, 50 mg/kg, 100 mg/kg og 200 mg/kg. Kontrollgruppen ble administrert buffret kokesaltoppløsning. 3 dager etter injeksjonen ble musene avlivet og peritoneal makrofager av dyrene på deres aktiveringstilstand ble undersøkt. Som mål for makrofag aktivering, ble det på den ene side bestemt sekresjonen av de lysomale enzymer (P-galactosidase, P-glucuronidase, N-acetyl-P-D-glucosaminidase). På den annen side kunne det i sammenhengbare makrofag-kulturer undersøkes pinozytose ved opptak av kolloidalt gull (<198>Au), slik det er kjent for fagfolk. Høyden av det oksydative stoffskiftet ved makrofager gjelder som et ytterligere mål for deres aktiveringstilstand. Denne aktivitet måles under hjelp av biolumater ved bestemmelse av chemoluminescens. Here, the impact of the test substance obtained according to embodiment examples 8 on the stimulation of peritoneal macrophages in 6-8 week old NMRI mice was investigated. Female mice received parenterally or orally the test substance in a dose of 25 mg/kg, 50 mg/kg, 100 mg/kg and 200 mg/kg. The control group was administered buffered saline solution. 3 days after the injection, the mice were sacrificed and peritoneal macrophages of the animals in their activation state were examined. As a measure of macrophage activation, the secretion of the lysosomal enzymes (P-galactosidase, P-glucuronidase, N-acetyl-P-D-glucosaminidase) was determined on the one hand. On the other hand, in confluent macrophage cultures, pinocytosis could be investigated by uptake of colloidal gold (<198>Au), as is known to those skilled in the art. The height of the oxidative metabolism of macrophages applies as a further measure of their activation state. This activity is measured with the help of biolumates by determining chemoluminescence.

For dette formål ble det kultivert enten i Petriskåler av For this purpose, it was cultured either in Petri dishes of

30 mm diameter 3 x IO<6> makrofager med 1 ml TC 199-kultur-medium eller også 10<6->makrofager med 100 pl i rundbue-polyetylensmårør (for bestemmelse av chemoluminiscens) ved 5% C02 og 37'C. 30 mm diameter 3 x 10<6> macrophages with 1 ml of TC 199 culture medium or also 10<6> macrophages with 100 µl in round arc polyethylene tubes (for determination of chemoluminescence) at 5% CO 2 and 37'C.

Etter en times virkning vaskes kulturene for å fjerne svømmende celler. Chemoluminescens (rørkulturen) bestemmes direkte, mens Petriskålene igjen ble dyrket 24 timer ved 37<*>C, og deretter ble det bestemt enzym- og pinozytose-aktivitet i kulturene. Det ble oppnådd følgende resultater. After one hour of action, the cultures are washed to remove floating cells. Chemoluminescence (the tube culture) is determined directly, while the Petri dishes were again cultivated for 24 hours at 37<*>C, and then enzyme and pinocytosis activity in the cultures was determined. The following results were obtained.

Den parenterale samt den orale behandling av NMRI-mus med det ifølge eksempel 8 fremstilte prøvestoff stimulerer makrofagaktiviteten og har dermed immunitetsstimulerende virkning. Således økes tydelig det oksydative stoffskiftet ved makrofager med generering av oksygenradikaler og de dermed forbundne målbare kryss. Ved doseringer fra 25 mg/kg oppad kommer det til en dosisavhengig økning av makrofagaktiviteten såvel ved parenteral som også oral applikasjon. The parenteral as well as the oral treatment of NMRI mice with the test substance prepared according to example 8 stimulates macrophage activity and thus has an immunity-stimulating effect. Thus, the oxidative metabolism of macrophages is clearly increased with the generation of oxygen radicals and the associated measurable junctions. At dosages from 25 mg/kg upwards, there is a dose-dependent increase in macrophage activity both with parenteral and oral application.

Av tabell 3 kan det sees at makrofager av kontrollmus bare har de små mengder av lysosomale enzymer (P-glucoronidase, p-galactosidase, N-acetyl-P-D-glucosaminidase) i det kultur-overstående. Mononukleære fagocytter fra mus som ble behandlet parenteralt eller oralt med prøvestoff i 72 timer, sezernerer de overnevnte sure hydrolaser (e-Glu, P-Gal, N-Ac-Glu) tydelig mer og har derved en dosisvirkningskurve som ved alle målte enzymer lar det fremgå en overlegenhet overfor kontrollene. Det sees at prøvestoffet har en stimulerende virkning på makrofagaktiviteten, og fører til økning av enzymfrigjøringen. From table 3 it can be seen that macrophages of control mice only have small amounts of lysosomal enzymes (P-glucoronidase, p-galactosidase, N-acetyl-P-D-glucosaminidase) in the culture supernatant. Mononuclear phagocytes from mice that were treated parenterally or orally with the test substance for 72 hours secrete the above-mentioned acid hydrolases (e-Glu, P-Gal, N-Ac-Glu) clearly more and thereby have a dose-response curve which, for all measured enzymes, allows show a superiority over the controls. It is seen that the test substance has a stimulating effect on macrophage activity, and leads to an increase in enzyme release.

Den kvantitative bestemmelse av pinozytoseaktiviteten ved mononukleære fagocytter ble gjennomført etter metoden til Davies et al, (Davies P. Allison, A.C. og Haswell, A.D. Biochem. Biophys. Res. Comm. 52, 627, 1973). Hertil ble det benyttet radioaktivt, kolloidalt gull (<198>Au) med en partikkelstørrelse på 20 nm, og en spesifikk aktivitet på 4-12 mCi/mg Au. Resultatene i tabell 4 viser effekten av det ifølge eksempel 8 dannede prøvestoff og endocytosedelsen. Pinozytosene av kolloidalt gull (<198>Au) ved muse-peritoneal-makrofager av en forbindelse fremstilt ifølge oppfinnelsen behandlede dyr er tydelig og dosisavhengig øket sammenlignet med makrofagene av ubehandlede dyr. The quantitative determination of the pinocytosis activity of mononuclear phagocytes was carried out according to the method of Davies et al, (Davies P. Allison, A.C. and Haswell, A.D. Biochem. Biophys. Res. Comm. 52, 627, 1973). For this, radioactive, colloidal gold (<198>Au) with a particle size of 20 nm, and a specific activity of 4-12 mCi/mg Au, was used. The results in table 4 show the effect of the test substance formed according to example 8 and the endocytosis. The pinocytosis of colloidal gold (<198>Au) by mouse peritoneal macrophages of animals treated with a compound prepared according to the invention is clearly and dose-dependently increased compared to the macrophages of untreated animals.

Eksperiment 3 Experiment 3

Økning av motstandskraften av balb/c-mus mot en Candida albicans infeksjon. Increasing the resistance of balb/c mice to a Candida albicans infection.

a) Profylaktisk behandling; Balb/c-mus ble over 4 dager i en dosering på 2 x 60 mg/kg/ dag behandling med intraperitoneal med prøvestoffet (forbindelse ifølge utførelseseksempelet 8). 24 timer etter siste administrering av prøvestoffet ble disse dyr og kontrolldyrene hvortil det var blitt administrert fysiologisk kokesaltoppløsning, i samme volum og tidsavsnitter infisert intravenøst med Candida albicans (5 x 10^ CFU/mus). Fra utdøingsgraden etter infeksjonen lar det seg tilsvarende beregne de midlere overlevelsestider. Dyrene av kontrollgruppen døde til 50 % etter 9,7 dager, de med prøvestoffet behandlede grupper viste en midlere overlevelsestid på 16,1 dag. I det valgte applikasjonsskjema med de tilsvarende doseringer (profylaktisk administrering) induserer prøvestoffet en tydelig økning av resistensen av Balb/c-mus overfor Candida albicans. a) Prophylactic treatment; Balb/c mice were treated intraperitoneally with the test substance (compound according to embodiment example 8) over 4 days at a dosage of 2 x 60 mg/kg/day. 24 hours after the last administration of the test substance, these animals and the control animals to which physiological saline solution had been administered, in the same volume and time intervals, were infected intravenously with Candida albicans (5 x 10^ CFU/mouse). From the degree of extinction after the infection, the mean survival times can be calculated correspondingly. The animals of the control group died to 50% after 9.7 days, the groups treated with the test substance showed a mean survival time of 16.1 days. In the chosen application scheme with the corresponding dosages (prophylactic administration), the test substance induces a clear increase in the resistance of Balb/c mice to Candida albicans.

b) Terapeutisk behandling: b) Therapeutic treatment:

Ved den terapeutiske behandling av en kronisk Candida albicans infeksjon ble hunn-Balb/c-mus (15/gruppe) ved dag 0 infisert intravenøst med Candida albicum (1 x 10 5 CFU/mus). Etter foretatt infeksjon ble dyrene på 8 etter hverandre følgende dager (dag 3-10) behandlet intraperitonealt med resp. 60 mg/kg av prøvestoffet (forbindelse ifølge utførelses-eksempel 8). Til kontrolldyrene ble det injisert fysiologisk kokesaltoppløsning. På dagené 8, 14 og 21 ble det tatt urinprøver av dyrene, og kimtallet bestemt. Ved dag 30 In the therapeutic treatment of a chronic Candida albicans infection, female Balb/c mice (15/group) were infected intravenously with Candida albicum (1 x 10 5 CFU/mouse) at day 0. After infection, the animals were treated intraperitoneally on 8 consecutive days (days 3-10) with resp. 60 mg/kg of the test substance (compound according to embodiment example 8). Physiological saline solution was injected into the control animals. On days 8, 14 and 21, urine samples were taken from the animals, and the germ count was determined. By day 30

ble dyrene avlivet og bestemt kimtall og nekrosedannelse i nyrene. Tabell 6 viste at prøvestoffet ved terapeutisk inngivning tydelig reduserer alle parametere av kronisk Candida albicum infeksjon (kimtall i urin og nyre og nekrosedannelse) , og dermed påvirke terapeutisk sykdommen. the animals were euthanized and the germ count and necrosis in the kidneys determined. Table 6 showed that the test substance, when administered therapeutically, clearly reduces all parameters of chronic Candida albicum infection (germ count in urine and kidney and necrosis formation), thereby influencing the disease therapeutically.

Mens kontrolldyrene lar seg påvise til en høy prosentsats kimer i urinen senkes ved de behandlede dyr kimtallet tydelig. While a high percentage of germs in the urine can be detected in the control animals, the germ count is clearly lowered in the treated animals.

Også kimbesetningen av dyrene reduseres ved terapien av 63 % til 27 %, ved en samtidig nedsettelse av nekrosedannelsen fra 87 % til 10 %. The germ population of the animals is also reduced by the therapy from 63% to 27%, with a simultaneous reduction in the formation of necrosis from 87% to 10%.

Eksperiment 4 Experiment 4

Stimulering av DTH-reaksjonen ved forbindelsen fremstilt ifølge oppfinnelsen. Stimulation of the DTH reaction by the compound produced according to the invention.

Som omtalt i eksperiment 1, ble NMRI-mus behandlet med stoffene fremstilt ifølge oppfinnelsen. As discussed in experiment 1, NMRI mice were treated with the substances prepared according to the invention.

Som prøve for å finne immunstimuleringen ble DTH-reaksjonen overprøvet. As a test to find the immune stimulation, the DTH reaction was tested.

Tabell 7 viser den relative virkning av prøvestoffet referert til forbindelsen fra eksempel 8, deres maksimale aktivering tilsvarer 100 %, (differens mellom kontroll og stimulering) . Av tabellen sees at DTH-reaksjonen ved de med prøvestoffene forbehandlede dyr er tydelig sterkere utpreget enn ved de tilsvarende kontrolldyr. Table 7 shows the relative effect of the test substance referred to the compound from example 8, their maximum activation corresponds to 100%, (difference between control and stimulation). The table shows that the DTH reaction in the animals pre-treated with the test substances is clearly stronger than in the corresponding control animals.

Eksempel 5 Example 5

Stimulering av makrofagenaktivitet ved forbindelsen fremstilt ifølge oppfinnelsen. Stimulation of macrophage activity by the compound produced according to the invention.

Som omtalt i eksperiment 2 ble NMRl-mus behandlet med forbindelsen fremstilt ifølge oppfinnelsen. As described in experiment 2, NMR1 mice were treated with the compound prepared according to the invention.

Som prøve for å finne immunstimuleringen ble funksjonen av makrofagene (chemoluminiszenz og enzymaktivitet) overprøvet. As a test to find the immune stimulation, the function of the macrophages (chemoluminiszenz and enzyme activity) was tested.

Tabell 8 Table 8

viser den relative virkning av prøvestoffene referert til forbindelsen fra eksempel 8, hvis maksimale aktivering (differans mellom kontroll og stimulering), tilsvarer 100 %. Av tabellen sees at i sammenligning av makrofager fra ubehandlede dyr var disse celler også sterkt stimulert med alle prøvestoffer i deres chemoluminescensreaksjon og tydelig øket i deres innhold av lysosomale enzymer. shows the relative effect of the test substances referred to the compound from example 8, whose maximum activation (difference between control and stimulation) corresponds to 100%. From the table it can be seen that in comparison of macrophages from untreated animals, these cells were also strongly stimulated with all test substances in their chemoluminescence reaction and clearly increased in their content of lysosomal enzymes.

Eksperiment 6 Experiment 6

Stimulering av infektforsvar mot Candida albicans infeksjoner ved profylaktisk inngivning av forbindelsen fremstilt ifølge o ppfinnelsen. Stimulation of infection defenses against Candida albicans infections by prophylactic administration of the compound produced according to the invention.

Som omtalt i eksperiment 3a ble Balb/c-mus behandlet med forbindelsen fremstilt ifølge oppfinnelsen. As discussed in experiment 3a, Balb/c mice were treated with the compound prepared according to the invention.

Som tabell 9 viser, øker den midlere overlevelsestid av musene etter C-a.lbicans-inf eks jon tydelig sammenlignet med en ubehandlet kontrollgruppe. As Table 9 shows, the mean survival time of the mice after C-a.lbicans infection clearly increases compared to an untreated control group.

Eksperiment 7 Experiment 7

Innvirkning på stimulering av tumorforsvar mot B16- melanom. Impact on stimulation of tumor defenses against B16 melanoma.

Hos hunn C57B1/6 mus (10 dyr/gruppe) med en vekt på 18-20 g ble det med 2 x 10 5 med levende B16 melanomceller indusert en primær tumorvekst. Etter utpregning av en bestemt tumor-størrelse, (0,65 cm i diameter) ble primærtumoren fjernet. De ubehandlede dyr døde deretter av metastaser i lungene. Etter tumorinduksjonen ble dyrene på dagene 3, 5, 7, 9, 11 og 13 etter amputasjon av primærtumoren, behandlet med 50, 100 og 200 mg/kg intraperitonelat av det ifølge eksempel 8 dannede prøvestoffer. Fra utdøingsgraden etter amputasjonen av primærtumoren, ved utviklingen av lungemetastaser, lar det seg beregne tilsvarende de midlere overlevelsestider. Ifølge dette dør dyrene av kontrollgruppen til 50 % etter In female C57B1/6 mice (10 animals/group) with a weight of 18-20 g, a primary tumor growth was induced with 2 x 10 5 of live B16 melanoma cells. After determining a specific tumor size (0.65 cm in diameter), the primary tumor was removed. The untreated animals then died of metastases in the lungs. After the tumor induction, the animals were treated on days 3, 5, 7, 9, 11 and 13 after amputation of the primary tumor with 50, 100 and 200 mg/kg intraperitoneally of the test substance produced according to example 8. From the degree of extinction after the amputation of the primary tumour, with the development of lung metastases, it is possible to calculate the corresponding average survival times. According to this, the animals of the control group die to 50% after

26 dager. De med prøvestoffer behandlede grupper viste 26 days. The groups treated with test substances showed

(sml. tabell 10) med de tilsvarende doseringer en tydelig økning av den midlere overlevningstidsforlengelse på 43, 40 og 35 dager. (cf. table 10) with the corresponding dosages a clear increase in the average survival time extension of 43, 40 and 35 days.

Eksperiment 8 Experiment 8

Innvirkning på benmargkolonidannelsen. Impact on bone marrow colonization.

Her ble det undersøkt innvirkningen av det ifølge eksempel 8 oppnådde prøvestoff på stimulering av benmargkoloniene Here, the impact of the test substance obtained according to example 8 on stimulation of the bone marrow colonies was investigated

ved 6-8 uker gamle B2D2Fl-mus. Hunn-mus fikk prøvestoffet intraperitonealt i dosene 2,5 og 5 mg/kg. En dag senere ble dyrene avlivet, benmargcellene isolert og kultivert etter de generelt kjente metoder (Metcalf, Immunology 21, 427, 1971 og Stanley et al, J. Exp. Med. 143, 631, 1979). in 6-8 week old B2D2Fl mice. Female mice received the test substance intraperitoneally in doses of 2.5 and 5 mg/kg. One day later the animals were killed, the bone marrow cells isolated and cultured according to the generally known methods (Metcalf, Immunology 21, 427, 1971 and Stanley et al, J. Exp. Med. 143, 631, 1979).

Til utvikling av benmargskoloniene ble det som "CSF"-kilde (Colony stimulating factor) som vanlig benyttet L-celle-overstående (15 %) . Koloniene ble talt 8 dager etter For the development of the bone marrow colonies, L-cell supernatant (15%) was used as a "CSF" source (Colony stimulating factor) as usual. Colonies were counted 8 days later

utsåing. Som det fremgår av tabell 11 fører engangs administrering av 2,5 eller 5 mg av prøvestoffet til en tydelig økning av kolonidannelsen ved benmargceller såvel med som også uten tilsetning av CSF (Colony stimulating factor) in vitro. seeding. As can be seen from table 11, a single administration of 2.5 or 5 mg of the test substance leads to a clear increase in colony formation by bone marrow cells, both with and without the addition of CSF (Colony stimulating factor) in vitro.

Følgende eksempler skal forklare oppfinnelsen nærmere. The following examples shall explain the invention in more detail.

Eksempel 1 Example 1

bis-( 3- hydroksy- l- feny1- 1, 2 , 4- triazol- 5- yl)- disulfid bis-(3-hydroxy-1-phenyl-1,2,4-triazol-5-yl)-disulfide

2,9 g (15 Mmol) 3-hydroksy-l-fenyl-5-merkapto-l,2,4-triazol haes i 2.9 g (15 mmol) of 3-hydroxy-1-phenyl-5-mercapto-1,2,4-triazole is added to

100 ml metanol og ved værelsestemperatur tildryppes 3,2 ml (33 Mmol) hydrogenperoksyd 35 %-ig i metanol. 100 ml of methanol and at room temperature 3.2 ml (33 Mmol) of 35% hydrogen peroxide in methanol are added dropwise.

Oppløsningen farver seg først gult, og etter 20 minutter faller den nye forbindelsen langsomt ut. Etter 4 timer frasuges utfellingen og vaskes med metanol og tørkes. The solution first turns yellow, and after 20 minutes the new compound slowly precipitates out. After 4 hours, the precipitate is suctioned off and washed with methanol and dried.

Utbytte: 2,1 g = 72 % av det teoretiske. Yield: 2.1 g = 72% of the theoretical.

Sm.p.: 232°C under spaltning. Melting point: 232°C during decomposition.

NMR (d^b-DMSO) 5 = 11,58 ppm, s, 2H, OH NMR (d^b-DMSO) δ = 11.58 ppm, s, 2H, OH

7,38 ppm, 10H, aromat, H. 7.38 ppm, 10H, aromatic, H.

Eksempel 2 Example 2

Bis-( 5- karboksy- benzimidazol- 2- yl)- disulfid Fremstilling analogt eksempel 1 fra 2-merkaptobenzimida-zol-5-karboksylsyre Bis-(5-carboxybenzimidazol-2-yl)disulfide Preparation analogous to example 1 from 2-mercaptobenzimidazole-5-carboxylic acid

Utbytte: 70 % av det teoretiske. Yield: 70% of the theoretical.

Sm.p.: 235-238°C. Melting point: 235-238°C.

NMR (dcb-DMSO) 6 = 9,4 ppm, d, NH, NMR (dcb-DMSO) 6 = 9.4 ppm, d, NH,

7,4 - 8,4 ppm, m, aromat, H. 7.4 - 8.4 ppm, m, aromatic, H.

Eksempel 3 Example 3

Bis-/~4-(2-klorallyl)-6-hydroksy-5-okso-4,5-dihydro-l,2,4-triazin- 3- yl7- disulf id. Bis-[4-(2-chloroallyl)-6-hydroxy-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl7-disulfide.

2,2 g 4-(2-klorallyl)-6-hydroksy-3-merkapto-5-okso-4,5-dihydro-1,2,4-triazin oppløses i 2.2 g of 4-(2-chloroallyl)-6-hydroxy-3-mercapto-5-oxo-4,5-dihydro-1,2,4-triazine are dissolved in

25 ml metanol, blandes ved værelsestemperatur dråpvis 25 ml of methanol, mix at room temperature dropwise

med with

0,86 ml 35 % I^C^ og etteromrører 1 time idet produktet utkrystalliserer. Det frasuges, vaskes med metanol og tørkes i luften. 0.86 ml of 35% I^C^ and stir for 1 hour as the product crystallizes. It is suctioned off, washed with methanol and dried in the air.

Utbytte 1,2 g Yield 1.2 g

Sm.p. 204-205°C under spaltning. Sm.p. 204-205°C during decomposition.

NMR (dg-DMSO) 6 = 12,7 ppm, (br. s, OH) NMR (dg-DMSO) 6 = 12.7 ppm, (br. s, OH)

5,5 ppm (dd, = CH2) 5.5 ppm (dd, = CH2)

4,8 ppm (s, CH2N). 4.8 ppm (s, CH2N).

Eksempel k Example k

Bis-(6-hydroksy-2-metyl-5-okso-2,5-dihydro-l,2,4-triazin-3-yl)- disulfid Bis-(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)- disulfide

1,59 g 6-hydroksy-3-merkapto-2-metyl-5-okso-2,5-di-hydro-l, 2,4-triazin oppløses i 1.59 g of 6-hydroxy-3-mercapto-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazine is dissolved in

30 ml metanol, og blandes ved værelsestemperatur dråpvis 30 ml of methanol, and mix at room temperature drop by drop

med with

0,43 ml 35 % H202 og ekstraomrøres i 30 minutter. Oppløs-ningen ble klargjort med kull, innrotert og re-siduet utdrevet med isvann. Utfellingen ble frafiltrert, vasket med isvann, tørket i luften, suspendert i metanol, frafiltrert, vasket med litt metanol, og tørket i vakuum. 0.43 ml 35% H202 and stirred for 30 minutes. The solution was prepared with charcoal, stirred in and the residue expelled with ice water. The precipitate was filtered off, washed with ice water, dried in air, suspended in methanol, filtered off, washed with a little methanol, and dried in vacuo.

Utbytte 0,8 g. Yield 0.8 g.

Sm.p. 200°C under spaltning. Sm.p. 200°C during decomposition.

NMR (dg-DMSO) 5 = 3,87 ppm (s, CH3). NMR (dg-DMSO) δ = 3.87 ppm (s, CH 3 ).

Eksempel 5 Example 5

Bis-(6-hydroksy-4-metyl-5-okso-4,5-dihydro-l,2,4-triazin-3- yl) - disulf id Bis-(6-hydroxy-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)-disulfide

3,7 g 6-hydroksy-3-merkapto-4-metyl-5-okso-4,5-dihydro-1,2,4-triazin ble oppløst i 3.7 g of 6-hydroxy-3-mercapto-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazine were dissolved in

400 ml metanol og 400 ml methanol and

38 ml H20. Ved værelsestemperatur ble det tildryppet 2,5 ml 35 % H202. Etter 30 minutters omrøringlble 38 ml of H20. At room temperature, 2.5 ml of 35% H2O2 was added dropwise. After 30 minutes of stirring

det inndampet til 100 ml, utfellingen frasuget og tørket. it evaporated to 100 ml, the precipitate was filtered off with suction and dried.

Utbytte 1,5 g, Yield 1.5 g,

Sm.p. 237°C Sm.p. 237°C

NMR (CF3C02D): 6 = 3,67 ppm, s. 2H, OH, NMR (CF 3 CO 2 D): δ = 3.67 ppm, p. 2H, OH,

3,8 ppm, s, 6H, CH^. 3.8 ppm, s, 6H, CH 2 .

Eksempel 5 Example 5

Bis-( 5- karboksymetyl- 4- metyl- tiazol- 2- yl)- disulfid Bis-(5-carboxymethyl-4-methyl-thiazol-2-yl)-disulfide

23,62 g 5-karboksymetyl-4-metyl-2-merkapto-tiazol ble 23.62 g of 5-carboxymethyl-4-methyl-2-mercaptothiazole were obtained

oppløst i dissolved in

250 ml metanol, filtrert og under vannbadavkjøling blandet 250 ml of methanol, filtered and mixed while cooling in a water bath

langsomt med slowly along

12,5 ml 35 % H2°2' Det ble etteromrørt 30 minutter i vannbad, og 2 timer ved værelsestemperatur. Etter filtrering og vasking med metanol, ble det isolert 22,8 g av tittelforbindelsen. 12.5 ml 35% H2°2' It was then stirred for 30 minutes in a water bath, and 2 hours at room temperature. After filtration and washing with methanol, 22.8 g of the title compound was isolated.

Sm.p. 162°C. Sm.p. 162°C.

NMR (CF3C02D): 6 = 2,6 ppm, s, 6H, CH3NMR (CF 3 CO 2 D): δ = 2.6 ppm, s, 6H, CH 3

4,2 ppm, s, 4H, CH2. 4.2 ppm, s, 4H, CH2.

Eksempel 7 Example 7

Bis-( 5- karboksymetyl- l, 3- tiazol- 2- yl)- disulfid Bis-(5-carboxymethyl-1,3-thiazol-2-yl)-disulfide

0,88 g 2-merkapto-l,3-tiazol-5-yl-eddiksyre oppløses i ca. 10 ml metanol, og blandes under omrøring ved værelsestemperatur med 0.88 g of 2-mercapto-1,3-thiazol-5-yl-acetic acid is dissolved in approx. 10 ml of methanol, and mixed with stirring at room temperature

0,5 ml 33 % Ho- 0 2-oppløsning. Etter 0,5 time ble krys-tallsuspensjonen avkjølt, filtrert, og filter-residuet tørket. Utbytte 0,6 g, sm.p. 15 0°C. Tynnsjiktkromatografisk sammenligning på Merck-Silikagelplater viser fullstendig omsetning (RF: 0,3, elueringsmiddel: eddikester: 6 5, etanol: 25, vann: 10, maursyre:l). 0.5 ml of 33% Ho-O 2 solution. After 0.5 hour, the crystalline suspension was cooled, filtered, and the filter residue dried. Yield 0.6 g, m.p. 15 0°C. Thin layer chromatographic comparison on Merck Silica gel plates shows complete conversion (RF: 0.3, eluent: acetic ester: 6 5, ethanol: 25, water: 10, formic acid: 1).

Eksempel 8 Example 8

Bis-( 4- karboksymetyl- l, 3- tiazol- 2- yl)- disulfid Bis-(4-carboxymethyl-1,3-thiazol-2-yl)-disulfide

omsetter man turnover

1,75 g 4-karboksymetyl-2-merkapto-tiazol analogt eksempel 1.75 g of 4-carboxymethyl-2-mercaptothiazole analogous example

8, så får man 0,95 g av tittelforbindelsen. 8, then 0.95 g of the title compound is obtained.

Sm.p. 163-165°C. Sm.p. 163-165°C.

NMR (DMSO-dc): 6 = 3,7 ppm, s, 4H, CH„ NMR (DMSO-dc): 6 = 3.7 ppm, s, 4H, CH„

7,6 ppm, s, 2H, CH 7.6 ppm, s, 2H, CH

9,4 ppm, s, 2H, CC^H. 9.4 ppm, s, 2H, CC₂H.

Eksempel 9 Example 9

Bis-( 2- karboksymetyl- tio- l, 3, 4- tiadiazol- 5- yl) - disulf id Bis-(2-carboxymethyl-thio-l,3,4-thiadiazol-5-yl)-disulfide

1,4 g 2-merkapto-l,2,3,4-tiadiazol-5-yl)merkaptoeddik-syre oppløses i 10 ml metanol og blandes dråpvis under isavkjøling med Dissolve 1.4 g of 2-mercapto-1,2,3,4-thiadiazol-5-yl)mercaptoacetic acid in 10 ml of methanol and mix dropwise under ice-cooling with

0,65 ml 35 % H2°2• Det etteromrøres 1 time ved værelsestemperatur og filtreres. Krystallene etter-vaskes med litt metanol og tørkes i vakuum. 0.65 ml 35% H2°2• Stir for 1 hour at room temperature and filter. The crystals are then washed with a little methanol and dried in a vacuum.

Utbytte: 1,3 g. Yield: 1.3 g.

Sm.p. 179°C under spaltning. Sm.p. 179°C during decomposition.

NMR (DMSO-dg) 6 = 13 ppm, bred, C02, NMR (DMSO-dg) 6 = 13 ppm, broad, CO 2 ,

4,2 ppm, s, CH2. 4.2 ppm, s, CH2.

Eksempel 10 Example 10

Bis-( 5- karboksy- l, 3- tiazol- 2- yl)- disulfid Bis-(5-carboxyl-1,3-thiazol-2-yl)-disulfide

21 g 2-merkapto-tiazol-5-karboksylsyre oppløses i 100 ml metanol under svak oppvarming. Under isavkjøling blandes langsomt med 21 g of 2-mercapto-thiazole-5-carboxylic acid are dissolved in 100 ml of methanol under gentle heating. During ice-cooling, slowly mix in

10,7 ml 35 % H202 og etteromrøres i 45 minutter ved værelsestemperatur. Det frasuges, vaskes med metanol og tørkes i vakuum. 10.7 ml of 35% H202 and stirred for 45 minutes at room temperature. It is suctioned off, washed with methanol and dried in a vacuum.

Utbytte: 21,5 g Yield: 21.5 g

Sm.p. 280°C under spaltning. Sm.p. 280°C during decomposition.

NMR (DMSO-dg): 6 = 8,48 ppm, s, tiazol-H. NMR (DMSO-dg): δ = 8.48 ppm, s, thiazole-H.

E k s e pi p e 1 11 E x p e p i p e 1 11

Bis-( 5- karboksy- 4- metyl- tiazol- 2- yl)- disulfid Bis-(5-carboxy-4-methyl-thiazol-2-yl)-disulfide

1,75 g (10 mmol) 4-metyl-2-merkapto-tiazol-5-karboksyl-syre oppslemmes i 1.75 g (10 mmol) of 4-methyl-2-mercapto-thiazole-5-carboxylic acid is suspended in

50 ml metanol og blandes under isavkjøling med 50 ml of methanol and mixed with ice-cooling

0,86 ml 35 % H202. Oppløsningen etteromrøres h time ved 0°C og 1 time ved værelsestemperatur. De dannede krystaller frasuges, vaskes med litt metanol og tørkes i vakuum. 0.86 mL 35% H2O2. The solution is then stirred for 1 hour at 0°C and 1 hour at room temperature. The formed crystals are suctioned off, washed with a little methanol and dried in a vacuum.

Utbytte: 1,52 g, sm.p. 240 - 241°C under spaltning. Yield: 1.52 g, m.p. 240 - 241°C during decomposition.

NMR (DMSO-dg): 6 = 2,6 ppm, s, CH3. NMR (DMSO- dg ): δ = 2.6 ppm, s, CH 3 .

Eksempel 1 2 Example 1 2

Bis-( 4- karboksymetyl- 5- metyl- tiazol- 2- yl)- disulfid Bis-(4-carboxymethyl-5-methyl-thiazol-2-yl)-disulfide

Trinn 1 Step 1

4- brompropionyleddiksyremetylester 4- Bromopropionylacetic acid methyl ester

22 g propionyleddiksyremetylester oppløses i 22 g of propionyl acetic acid methyl ester are dissolved in

60 g CH2C12 og blandes dråpvis med 60 g CH2C12 and mix dropwise with

8,7 ml Br2 i 8.7 mL of Br2 i

30 ml CH2C12. Det etteromrøres i 1/4 time ved værelsestemperatur. Det blandes igjen med 30 mL of CH 2 Cl 2 . It is then stirred for 1/4 hour at room temperature. It is mixed again with

0,66 ml Br2 i 0.66 mL of Br2 i

5 ml CH2<_12, og omrøres ytterligere 1 1/4 time 5 ml of CH2<_12, and stirred for a further 1 1/4 hours

Det vaskes 3 ganger med resp. It is washed 3 times with resp.

50 ml H20' en 9an(? med 50 ml H20' a 9an(? with

20 ml mettet NaHCO^ og 2 ganger med resp. 20 ml saturated NaHCO^ and 2 times with resp.

50 ml H2°2' tc5rlces over Na2S04 og inndampes. Man får 38,6 g olje. 50 ml of H2°2' tc5rlces over Na2SO4 and evaporated. You get 38.6 g of oil.

Trinn 2 Step 2

( 2- merkapto- 5- metyl)- tiazol- 4- yl)- eddiksyremetylester ( 2- mercapto- 5- methyl)- thiazol- 4- yl)- acetic acid methyl ester

30,1 g av oljen fra trinn 1, oppløst i 30.1 g of the oil from step 1, dissolved in

80 ml etanol, tildryppes til en oppløsning av 80 ml of ethanol, added dropwise to a solution of

24 g nytilberedt ammoniumditiokarbaminat i 200 ml etanol/ 24 g freshly prepared ammonium dithiocarbamate in 200 ml ethanol/

200 ml K202 ved værelsestemperatur. Det etteromrøres så 200 ml K202 at room temperature. It is then stirred

h time og blandes med h hour and mixed with

7,5 ml trifluoreddiksyre. Etter 1 times etteromrøring 7.5 ml of trifluoroacetic acid. After 1 hour of stirring

inndampes til tørrhet, og blandes med evaporated to dryness, and mixed with

200 ml CHC1_/H20 (1:1). Det vaskes ennå to ganger med H20, 200 mL CHCl_/H 2 O (1:1). It is further washed twice with H20,

tørkes over Na2S04 og inndampes. Det faste residu oppslemmes i eter og frafiltreres. dried over Na2S04 and evaporated. The solid residue is suspended in ether and filtered off.

Utbytte 8,9 g, Yield 8.9 g,

Sm.p. 149°C under spaltning, Sm.p. 149°C during decomposition,

NMR (dg-DMSO): 6 = 11 ppm, bred, SH NMR (dg-DMSO): δ = 11 ppm, broad, SH

3.7 ppm, S, OCH3, 3.7 ppm, S, OCH3,

3,5 ppm, s, CH2, 3.5 ppm, s, CH2,

2,1 ppm, S, CH3. 2.1 ppm, S, CH3.

Trinn 3 Step 3

( 2- merkapto- 5- metyl- tiazol- 4- yl)- eddiksyre (2-mercapto-5-methyl-thiazol-4-yl)-acetic acid

1,98 g av trinn 2 ble oppløst under oppvarming i 20 ml metanol. Det etteromrøres 40 minutter ved værelsestemperatur, blandes med 1.98 g of step 2 was dissolved under heating in 20 ml of methanol. It is then stirred for 40 minutes at room temperature, mixed with

50 ml H20 og surgjøres med HC1 kons. til pH 1,0. Etter 50 ml H20 and acidified with HC1 conc. to pH 1.0. After

1 times omrøring under isavkjøling, ble det frasuget og vasket klorfritt med isvann. Tørkning i vakuum over P2°5 qa l'*>7 g. Stirring under ice cooling for 1 hour, it was suctioned off and washed free of chlorine with ice water. Drying in vacuum over P2°5 qa l'*>7 g.

NMR (dg-DMSO): 6 = 13,9 ppm, bred, C02H NMR (dg-DMSO): δ = 13.9 ppm, broad, CO 2 H

3,5 ppm, s, CH23.5 ppm, s, CH2

2.08 ppm, s, CH3. 2.08 ppm, s, CH3.

Trinn 4 Step 4

Bis-( 4- karboksymetyl- 5- metyl- tiazol- 2- yl)- disulfid Bis-(4-carboxymethyl-5-methyl-thiazol-2-yl)-disulfide

430 mg av trinn 3 ble suspendert i 430 mg of step 3 was suspended in

20 ml metanol og oppløst under oppvarming. Ved værelsestemperatur ble det tildryppet 20 ml of methanol and dissolved under heating. At room temperature it was added drop by drop

0,25 ml 35 % ^ 2°2 0<^ etteromrørt ennå 1 time. Etter inndampning til ca. 5 ml, ble det filtrert, og vasket med litt isavkjølt metanol. 0.25 ml 35% ^ 2°2 0<^ stirred for a further 1 hour. After evaporation to approx. 5 ml, it was filtered and washed with a little ice-cooled methanol.

Utbytte: 280 mg Yield: 280 mg

NMR (dg-DMSO): 5 = 3,65 ppm, s, CH2, NMR (dg-DMSO): δ = 3.65 ppm, s, CH2,

2,37 ppm, s, CH3. 2.37 ppm, s, CH 3 .

Eksemoel 13 Example 13

Bis-( 5- karboksymetyl- l, 3- diazol- 2- yl)- disulfid Bis-(5-carboxymethyl-1,3-diazol-2-yl)-disulfide

0,8 g 2-merkapto-5-karboksymetyl-l,3-tiazol ble oppløst i 10 ml metanol og blandet under omrøring dråpvis med 0,5 ml 33 %-ig H202-oppløsning. Man lar det omrøre natten over og frafiltrerer det utkrystalli-serte produkt. 0.8 g of 2-mercapto-5-carboxymethyl-1,3-thiazole was dissolved in 10 ml of methanol and mixed with stirring dropwise with 0.5 ml of 33% H 2 O 2 solution. It is allowed to stir overnight and the crystallized product is filtered off.

Utbytte: 0,6 g,av sm.p. 150°C under spaltning, tynnsjiktkromatografisk enhetlig (Rf = 0,3, kiselgel, elueringsmiddel:eddikester/etanol, vann, maursyre (60: 25:15:1). Yield: 0.6 g, of m.p. 150°C during decomposition, thin-layer chromatographic uniform (Rf = 0.3, silica gel, eluent: acetic ester/ethanol, water, formic acid (60: 25:15:1).

IR (KBr-presslegeme): y = 1710 cm (COOH). IR (KBr press body): y = 1710 cm (COOH).

<1>H-NMR (d^-DMSO): 6 (ppm): 3,8 (s, CH_-tiazol, 2H), <1>H-NMR (d^-DMSO): 6 (ppm): 3.8 (s, CH_-thiazole, 2H),

7,6 (s, tiazol-4H, 1H). 7.6 (s, thiazole-4H, 1H).

Eksempel lh Example lh

Bis-( 4- karboksy- l, 3- tiazol- 5- yl)- disulfid Bis-(4-carboxyl-1,3-thiazol-5-yl)-disulfide

5 g bis-(4-metoksykarbonyl-l,3-tiazol-5-yl)-disulfid ble suspendert i 100 ml metanol. Dertil satte man en oppløsning av 1,5 g NaOH i 20 ml H202 oppvarmet 1 time under tilbakeløp. Etter oppløsningens avkjøling ble metanol fjernet på rotasjonsfordamper, vannfasen ekstra-hert en gang med litt eddikester, og surgjort med 2-n HC1. Produktet ble frafiltrert, tørkes og om-krystallisert fra eddikester.. Man får 2 g av sm.p. 154°C. 5 g of bis-(4-methoxycarbonyl-1,3-thiazol-5-yl)-disulfide was suspended in 100 ml of methanol. To this was added a solution of 1.5 g of NaOH in 20 ml of H 2 O 2 heated for 1 hour under reflux. After cooling the solution, methanol was removed on a rotary evaporator, the aqueous phase was extracted once with a little vinegar, and acidified with 2-n HCl. The product was filtered off, dried and recrystallized from acetic acid. 2 g of m.p. 154°C.

IR (KBr-presslegeme): y = 1680 cm<-1> (COOH) IR (KBr press body): y = 1680 cm<-1> (COOH)

<1>H-NMR (d6-DMSO): 6 (ppm), 8,6 (s, tiazol-2H). <1>H-NMR (d 6 -DMSO): 6 (ppm), 8.6 (s, thiazole-2H).

Eksemplene 15 til 17 ble utført som omtalt i eksempel 1. Examples 15 to 17 were carried out as discussed in Example 1.

Eksempel 15 Example 15

Bis-( 1, 3- tiazdl- 5- glutarsyremonoamid- 2- yl)- disulfid Bis-(1,3-thiazdl-5-glutaric acid monoamid-2-yl)-disulfide

<1>H-NMR (dg - DMSO): <1>H-NMR (dg - DMSO):

6 = 1,6 - 2,6 ppm (m 12H, seks CH^-grupper), 7,50 ppm (s, 2H), tiazol-H), 12,63 ppm (br s, 2H, -NH-), 13,05 ppm (br s, 2H, -C02H). 6 = 1.6 - 2.6 ppm (m 12H, six CH^ groups), 7.50 ppm (s, 2H), thiazole-H), 12.63 ppm (br s, 2H, -NH-) , 13.05 ppm (br s, 2H, -CO 2 H).

Eksempel 16 Example 16

Bis-( 1, 3- tiazol- 5- ravsyremonoamid- 2- yl)- disulfid Bis-(1,3-thiazol-5-succinic acid monoamid-2-yl)-disulfide

1H-NMR (dc - DMSO): 1H-NMR (dc - DMSO):

b b

6 = 2,4 - 2,7 ppm (m, 8H, -CH2), 7,50 ppm (s, 2H, tiazol-H), 12,66 ppm (br s, 2H, -NH-), 13,15 ppm (br s, 2H, -S02H). Eksempel 17 /~ 5-( 2- karboksyet- l- yl)- 4- metyl- l, 3- tiazol- 2- yl7- disulfid 1H-NMR (dg - DMSO): 6 = 2,27 ppm (s, 6H, -CH ) , 2,55 ppm (d, 4H, tiazol-CH-,) , 2,96 ppm (t, 4H, CH2-C02). 6 = 2.4 - 2.7 ppm (m, 8H, -CH2), 7.50 ppm (s, 2H, thiazole-H), 12.66 ppm (br s, 2H, -NH-), 13, 15 ppm (br s, 2H, -SO 2 H). Example 17 /~ 5-(2-carboxyethyl-1-yl)-4-methyl-1,3-thiazol-2-yl7-disulfide 1H-NMR (dg - DMSO): 6 = 2.27 ppm (s, 6H , -CH ) , 2.55 ppm (d, 4H, thiazole-CH-,) , 2.96 ppm (t, 4H, CH 2 -CO 2 ).

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutisk aktive disulfider for immunstimulasjon, immunrestaurasjon og cytostatisk behandling med den generelle formel hvori Het' betyr 1,3-tiazolyl, som er substituert med C^-Cg-alkyl, karboksy-C^-Cg-alkyl, karboksy eller C2-C5-acylamino, idet acyl er resten av en alifatisk dikarboksylsyre; eller 1,2,4-triazolyl, som er substituert med hydroksy og fenyl; eller 1,3,4-tiadiazolyl, som er substituert med karboksy Ci-C4-alkyltio; eller dihydro-1,2,4-triazinyl, som er substituert med C^-Cg-alkyl, halogeno-C2-C4-alkenyl, okso eller hydroksy eller benzimidazolyl, som er substituert med karboksy; idet Het' er substituert med minst en direkte eller til en substituent-bundet karboksygruppe eller en direktebundet hydroksygruppe, idet disse begge gruppene kan foreligge i form av et fysiologisk tålbart salt, karakterisert ved at a) en forbindelse med formel II hvor Het' som har ovennevnte betydning, ved omsetning med et oksydasjonsmiddel overføres til en forbindelse med formel I' eller b) en forbindelse med formel III<_>t>Analogous process for the preparation of therapeutically active disulfides for immunostimulation, immunorestoration and cytostatic treatment of the general formula wherein Het' means 1,3-thiazolyl, which is substituted with C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkyl, carboxy or C2-C5 acylamino, acyl being the residue of an aliphatic dicarboxylic acid; or 1,2,4-triazolyl, which is substituted with hydroxy and phenyl; or 1,3,4-thiadiazolyl, which is substituted with carboxy C 1 -C 4 alkylthio; or dihydro-1,2,4-triazinyl, which is substituted by C 1 -C 8 -alkyl, halogeno-C 2 -C 4 -alkenyl, oxo or hydroxy or benzimidazolyl, which is substituted by carboxy; in that Het' is substituted with at least one directly or to a substituent-bonded carboxy group or a directly bonded hydroxy group, in that both of these groups can be present in the form of a physiologically tolerable salt, characterized in that a) a compound of formula II where Het' which has above meaning, by reaction with an oxidizing agent is transferred to a compound of formula I' or b) a compound of formula III<_>t> hvori Het' har ovennevnte betydning, og X betyr en reaktiv lett avspaltbar gruppe, omsettes med Me2S2, idet Me betyr et alkalimetall eller c) en forbindelse med formel IVin which Het' has the above meaning, and X means a reactive easily cleavable group, reacted with Me2S2, Me meaning an alkali metal or c) a compound of formula IV hvori Het' og Me har ovennevnte betydning, omsettes med jod i vandig medium.in which Het' and Me have the above meaning, is reacted with iodine in an aqueous medium.
NO860908A 1985-03-12 1986-03-11 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DISULFIDES NO168357C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19853508666 DE3508666A1 (en) 1985-03-12 1985-03-12 HETEROCYCLIC DISULFIDES AND THEIR USE AS IMMUNO MODULATORS

Publications (3)

Publication Number Publication Date
NO860908L NO860908L (en) 1986-09-15
NO168357B true NO168357B (en) 1991-11-04
NO168357C NO168357C (en) 1992-02-12

Family

ID=6264871

Family Applications (1)

Application Number Title Priority Date Filing Date
NO860908A NO168357C (en) 1985-03-12 1986-03-11 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DISULFIDES

Country Status (19)

Country Link
EP (1) EP0194571B1 (en)
JP (1) JPH0751572B2 (en)
KR (1) KR940001773B1 (en)
AR (1) AR245113A1 (en)
AT (1) ATE58293T1 (en)
AU (1) AU594943B2 (en)
DE (2) DE3508666A1 (en)
DK (1) DK165181C (en)
ES (3) ES8801506A1 (en)
FI (1) FI860980A (en)
GR (1) GR860649B (en)
HU (1) HU201742B (en)
IE (1) IE58729B1 (en)
IL (1) IL78091A (en)
NO (1) NO168357C (en)
NZ (1) NZ215424A (en)
PH (1) PH22275A (en)
PT (1) PT82166B (en)
ZA (1) ZA861780B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3915094A1 (en) 1989-05-09 1991-01-10 Hoechst Ag PROCESS FOR THE PREPARATION OF 2-MERCAPTO-4-METHYL-1,3-THIAZOL-5-YL-ACETIC ACID AND THEIR ESTERS
TW252112B (en) * 1993-08-19 1995-07-21 Pfizer
DE10055219A1 (en) 2000-11-08 2002-05-29 Bayer Ag Process for the preparation of dithiazolyl disulfides
US8163776B2 (en) 2001-01-10 2012-04-24 Grassetti Family Trust Method of immunomodulation using thione-forming disulfides
DE102005004472A1 (en) * 2005-01-31 2006-08-10 Rhein Chemie Rheinau Gmbh Process for the preparation of bis-DMTD

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR5680M (en) * 1966-08-19 1968-01-08
IL36587A (en) * 1970-05-05 1977-10-31 Grassetti D Compositions containing pyridine derivatives and their use in a method of modifying cellular surface reactions
US4378364A (en) * 1970-05-05 1983-03-29 Grassetti Davide R Postoperative treatment of carcinoma patients
GB1365943A (en) * 1970-09-16 1974-09-04 Gaf Corp Metalworking additive and composition and process for making the same
GB1327467A (en) * 1970-10-12 1973-08-22 Merck & Co Inc Pharmaceutical compositions for inhibiting indoleamine- n-methyl transferase
FR2403798A1 (en) * 1977-09-22 1979-04-20 Rorer Inc William H SYNERGIC COMPOSITIONS BASED ON BIS (2-PYRIDYL-1-OXIDE) DISULPHIDE AND THEIR USE FOR THEIR ANTI-INFLAMMATORY ACTIVITY
US4152439A (en) * 1978-01-12 1979-05-01 Davide R. Grassetti Stimulant and antidepressant agents
DE2944225A1 (en) * 1979-11-02 1981-05-07 Akzo Gmbh, 5600 Wuppertal METHOD FOR PRODUCING DITHIAZOL DISULFIDES
US4451471A (en) * 1981-03-18 1984-05-29 Ciba-Geigy Corporation Certain 2,4,5-tri-substituted thiazoles, pharmaceutical compositions containing same and methods of using same
DE3118128A1 (en) * 1981-05-07 1982-12-02 Bayer Ag, 5090 Leverkusen Use of disulphides as lipoxygenase inhibitors and pharmaceutical compositions containing these
DE3263149D1 (en) * 1981-10-21 1985-05-23 Beecham Group Plc Topical antimicrobial compositions
HU193951B (en) * 1985-03-11 1987-12-28 Richter Gedeon Vegyeszet Process for producing new sulfur-containing 5-substituted benzimidazol derivatives and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
ES8801506A1 (en) 1988-01-16
DK108786A (en) 1986-09-13
ES557615A0 (en) 1988-02-16
AR245113A1 (en) 1993-12-30
PT82166A (en) 1986-04-01
IL78091A0 (en) 1986-07-31
ES8801624A1 (en) 1988-02-16
NO168357C (en) 1992-02-12
EP0194571B1 (en) 1990-11-14
ES552840A0 (en) 1988-01-16
DK108786D0 (en) 1986-03-10
PT82166B (en) 1988-07-29
FI860980A0 (en) 1986-03-10
FI860980A (en) 1986-09-13
DE3675561D1 (en) 1990-12-20
AU5460586A (en) 1986-10-16
KR860007246A (en) 1986-10-10
EP0194571A1 (en) 1986-09-17
AU594943B2 (en) 1990-03-22
IE58729B1 (en) 1993-11-03
DE3508666A1 (en) 1986-09-18
DK165181C (en) 1993-03-01
ES557614A0 (en) 1988-02-16
ZA861780B (en) 1986-10-29
ES8801625A1 (en) 1988-02-16
IL78091A (en) 1990-04-29
JPH0751572B2 (en) 1995-06-05
DK165181B (en) 1992-10-19
GR860649B (en) 1986-07-11
JPS61207331A (en) 1986-09-13
IE860630L (en) 1986-09-12
ATE58293T1 (en) 1990-11-15
HU201742B (en) 1990-12-28
NO860908L (en) 1986-09-15
PH22275A (en) 1988-07-14
KR940001773B1 (en) 1994-03-05
NZ215424A (en) 1989-04-26

Similar Documents

Publication Publication Date Title
US7960427B2 (en) 5-hydroxyindole-3-carboxylate derivatives and uses thereof
US20050197375A1 (en) Use of benzimidazole analogs in the treatment of cell proliferation
JP6746605B2 (en) Method for making oxathiazine-like compounds
PL146070B1 (en) Method of obtaining 2-/n-substituted guanidin/4-/1,2,4-triazol-5-il/-thiazoles
JP2023171614A (en) Aldose reductase inhibitors and methods of use thereof
JP3539926B2 (en) Antiviral pyrimidinedione derivatives and methods for their production
AU3030399A (en) Nitrate salt of anti-ulcer medicine
US6476059B1 (en) Use of polycyclic 2-aminothiazole systems for the treatment of obesity
NO168357B (en) ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DISULFIDES
US4590205A (en) Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes
US4762848A (en) 1,3-thiazoles and their use as immunomodulators
TW200529809A (en) HIV protease inhibiting compounds
EP0087629A2 (en) Antiinflammatory and/or analgesic 2,3-Diaryl-5-halo thiophenes
US6329407B1 (en) Use of polycyclic thiazole systems for the treatment of obesity
CN115515603A (en) Bicyclic and monocyclic nucleoside analogs for the treatment of hepatitis E
AU679305B2 (en) Substituted cyclohexanol esters, their use for treating diseases, and pharmaceutical preparations
JPWO2008047769A1 (en) Glucose metabolism improver
US20220098134A1 (en) Antihypertensive polyol compound and derivative thereof
CA1292990C (en) Heterocyclic disulfides and their use as immunomodulators
NO179005B (en) Analogous Process for Preparation of Therapeutically Active 1,2,4-Benzotriazine Oxides
HU191496B (en) Process for producing derivates 2-guanidino-4thiazolyl-thiazoles
JPH04224557A (en) Substituted acetoamide derivative and antiulcer agent containing the same
MXPA01007452A (en) Utilization of polycyclic 2-amino-thiazole systems in the production of medicaments for prophylaxis or treatment of obesity
MXPA01007281A (en) Polycyclic 2-amino-thiazole systems, method for the production thereof and medicament containing said compounds