NO133141B - - Google Patents

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NO133141B
NO133141B NO3797/68A NO379768A NO133141B NO 133141 B NO133141 B NO 133141B NO 3797/68 A NO3797/68 A NO 3797/68A NO 379768 A NO379768 A NO 379768A NO 133141 B NO133141 B NO 133141B
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general formula
compound
chloro
alkyl
above meaning
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NO3797/68A
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Norwegian (no)
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NO133141C (en
Inventor
S Umio
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Fujisawa Pharmaceutical Co
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Publication of NO133141C publication Critical patent/NO133141C/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • C07D235/26—Oxygen 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av nye, terapeutisk aktive benzotiazol- og benzimidazolforbindelser med den generelle formel The present invention relates to an analogue method for the production of new, therapeutically active benzothiazole and benzimidazole compounds with the general formula

hvori Z er svovel eller lavere alkylimino, wherein Z is sulfur or lower alkylimino,

A er alkylen med 1-3 karbonatomer, fortrinnsvis metylen, R er hydrogen, halogen, lavere alkyl, lavere alkoksy A is the alkylene with 1-3 carbon atoms, preferably methylene, R is hydrogen, halogen, lower alkyl, lower alkoxy

eller trifluormetyl, or trifluoromethyl,

R 2er hydrogen eller lavere alkyl, R 2 is hydrogen or lower alkyl,

R 3 er 1avere' alkyl, halo(lavere)alkyl, hydroksy(lavere) R 3 is lower alkyl, halo(lower)alkyl, hydroxy(lower)

alkyl, lavere alkanoyloksy(lavere)alkyl, lavere alkoksy-(lavere)alkyl, hydroksy(lavere)alkoksy(1 avere)alkyl, alkyl, lower alkanoyloxy(lower) alkyl, lower alkoxy-(lower) alkyl, hydroxy(lower) alkoxy(1 avere) alkyl,

hydroksyfenyl, eller en gruppe med den generelle formel hydroxyphenyl, or a group of the general formula

4 5 hvori A<*> er lavere alkylen og R og R er hver lavere alkyl eller cykloalkyl med 3-6 karbonatomer, eller gruppen med formelen: står enten for aziridinyl, piperidino som kan være substituert med hydroksy, eller piperazinyl som kan være substituert med opp til 2 lavere alkylradikaler og nitrogenatomet i 4-stillingen kan i tillegg være substituert med lavere alkyl, hydroksy(lavere)alkyl, lavere alkanoyl(lavere)alkyl, lavere alkanoyloksy(lavere)alkyl eller lavere alkoksykarbonyl (lavere)alkyl, idet R 1 ikke er hydrogen når R 2 og R 3 hver er lavere alkyl eller 4 5 in which A<*> is lower alkylene and R and R are each lower alkyl or cycloalkyl of 3-6 carbon atoms, or the group of the formula: represents either aziridinyl, piperidino which may be substituted with hydroxy, or piperazinyl which may be substituted with up to 2 lower alkyl radicals and the nitrogen atom in the 4-position can additionally be substituted with lower alkyl, hydroxy(lower)alkyl, lower alkanoyl(lower)alkyl, lower alkanoyloxy(lower)alkyl or lower alkoxycarbonyl (lower)alkyl, where R 1 is not hydrogen when R 2 and R 3 are each lower alkyl or

står for aziridinyl eller piperidino. stands for aziridinyl or piperidino.

Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at enten The peculiarity of the method according to the invention is that either

(a) en forbindelse med den generelle formel (a) a compound of the general formula

hvori Z og R"*" har den ovennevnte betydning, eller et reaktivt derivat derav, omsettes med et alkylhalogenid med den generelle formel in which Z and R"*" have the above meaning, or a reactive derivative thereof, is reacted with an alkyl halide of the general formula

hvori X er halogen, R 2 og R 3 samt A har den ovennevnte betydning, eller in which X is halogen, R 2 and R 3 and A has the above meaning, or

(b) en forbindelse med den generelle formel hvori Z, A og R har den ovennevnte betydning, eller et salt eller et reaktivt derivat derav, omsettes med et amin med den generelle formel (b) a compound of the general formula in which Z, A and R have the above meanings, or a salt or reactive derivative thereof, is reacted with an amine of the general formula

2 3 2 3

hvori R og R har den ovennevnte betydning, wherein R and R have the above meaning,

bg om ønsket for fremstilling av en forbindelse med den generelle formel bg if desired for the preparation of a compound of the general formula

hvori R 1 , R 2, Z, X, A og A<1> har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel hvori R 1 , R 2, Z, A og A' har den ovennevnte betydning, med et halogeneringsmiddel, eller om ønsket, for fremstilling av en forbindelse med den generelle formel hvori R"*" , Z og A har den ovennevnte betydning og B er 2 7 8 hvori R har den ovennevnte betydning og R og R hver er hydrogen eller lavere alkyl, A'•• er lavere alkylen og R <9>er lavere alkanoyl, omsettes en erholdt forbindelse med den generelle formel hvori R<1>, Z, A, B og A1" har den ovennevnte betydning, med et alkanoyleringsmiddel, eller om ønsket, for fremstilling av en forbindelse med den generelle formel hvori X' er halogen og Z, A og R<1> har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel hvori A, Z og R''" har den ovennevnte betydning, med en hydrohalogensyre, eller om ønsket, for fremstilling av en forbindelse med den generelle formel 14 5 hvori A, Z, R , R og R har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel hvori A, Z og R<*> har den ovennevnte betydning, med et amin med den generelle formel in which R 1 , R 2 , Z, X, A and A<1> have the above-mentioned meaning, an obtained compound is reacted with the general formula in which R 1 , R 2 , Z, A and A' have the above-mentioned meaning, with a halogenating agent, or if desired, for the preparation of a compound of the general formula wherein R"*" , Z and A have the above meaning and B is 2 7 8 wherein R has the above meaning and R and R are each hydrogen or lower alkyl , A'•• is lower alkylene and R <9> is lower alkanoyl, an obtained compound of the general formula in which R<1>, Z, A, B and A1" has the above meaning is reacted with an alkanoylating agent, or if desired, for the preparation of a compound of the general formula in which X' is halogen and Z, A and R<1> have the above-mentioned meaning, an obtained compound of the general formula in which A, Z and R''" have the above-mentioned meaning, with a hydrohalic acid, or if desired, for the preparation of a compound of the general formula 14 5 in which A, Z, R , R and R has the above-mentioned meaning, a compound obtained with the general formula in which A, Z and R<*> have the above-mentioned meaning is reacted with an amine of the general formula

hvori R-^ og R^ har den ovennevnte betydning, eller wherein R-^ and R^ have the above meaning, or

om ønsket, for fremstilling av en forbindelse med den generelle formel if desired, for the preparation of a compound of the general formula

12 4 5 hvori A, Z, A<*>, R , R , R og R har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel 1 2 hvori X'' er halogen og Z, A, A', R og R har den ovennevnte betydning, med et amin med den generelle formel 12 4 5 in which A, Z, A<*>, R , R , R and R have the above meaning, a compound obtained is reacted with the general formula 1 2 in which X'' is halogen and Z, A, A', R and R has the above meaning, with an amine of the general formula

4 5 4 5

hvori R og R har den ovennevnte betydning, eller wherein R and R have the above meaning, or

om ønsket, for fremstilling av en forbindelse med den generelle formel if desired, for the preparation of a compound of the general formula

6 1 V 8 hvori R er hydrogen eller lavere alkyl og Z, A, R , R og R har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel 17 8 hvori Z, A, R , R og R har den ovennevnte betydning, med et alkylenoksyd med den generelle formel 6 1 V 8 in which R is hydrogen or lower alkyl and Z, A, R , R and R have the above meaning, an obtained compound is reacted with the general formula 17 8 in which Z, A, R , R and R have the above meaning , with an alkylene oxide of the general formula

hvori R har den ovennevnte betydning, eller wherein R has the above meaning, or

om ønsket, for fremstilling av en forbindelse med den generelle formel if desired, for the preparation of a compound of the general formula

1 7 8 hvori A* * er lavere alkylen, Z, A, R , R og R har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel 17 8 hvori Z, A, R , R og R har den ovennevnte betydning, med en haloalkanol med den generelle formel hvori X''' er halogen og A'<1> har den ovennevnte betydning, eller om ønsket, for fremstilling av en forbindelse med den generelle formel hvori A1 ' ' betyr lavere alkylen og R alkyl med tilsammen høyst 6 karbonatomer, og Z, A og R<1> har den ovennevnte betydning, reduseres en erholdt forbindelse med den generelle formel hvori Z, A, A<11>', R"*" og R har den ovennevnte betydning, med et reduksjonsmiddel, eller om ønsket, for fremstilling av en forbindelse med den generelle formel hvori Z, A, A''<1>, B og R<1> har den ovennevnte-betydning, reduseres en erholdt forbindelse med den generelle formel 1 7 8 in which A* * is lower alkylene, Z, A, R , R and R have the above meaning, an obtained compound is reacted with the general formula 17 8 in which Z, A, R , R and R have the above meaning, with a haloalkanol of the general formula in which X''' is halogen and A'<1> has the above meaning, or if desired, for the preparation of a compound of the general formula in which A1'' means lower alkylene and R alkyl together with at most 6 carbon atoms, and Z, A and R<1> have the above-mentioned meaning, a compound obtained with the general formula is reduced in which Z, A, A<11>', R"*" and R have the above-mentioned meaning, with a reducing agent, or if desired, for the preparation of a compound of the general formula in which Z, A, A''<1>, B and R<1> have the above meaning, an obtained compound of the general formula is reduced

hvori R<11> er lavere alkyl og Z, A, A'<11>, B og R<1> har den ovennevnte betydning, med et reduksjonsmiddel. wherein R<11> is lower alkyl and Z, A, A'<11>, B and R<1> have the above meaning, with a reducing agent.

Det er tidligere ikke påvist at benzotiazol- og benzimidazol-forbindelser kan ha antiinf1ammatorisk og/eller antiarhytmisk virkning, idet slik virkning tidligere ikke er påvist i forbindelse med denne type forbindelser. It has not previously been demonstrated that benzothiazole and benzimidazole compounds can have anti-inflammatory and/or antiarrhythmic effects, as such effects have not previously been demonstrated in connection with this type of compounds.

Den typiske og kraftige antiinflammatoriske virkning er påvist The typical and powerful anti-inflammatory effect has been demonstrated

ved motvirkning av svelling indusert ved hjelp av formalin, albumin og carragenin i rottepoter, og forbindelsene er også påvist å ha en inhiberende virkning ved passiv kutan anafylakse fremkalt ved injeksjon av antigen (egg-albumin) i rotter. by counteracting swelling induced by formalin, albumin and carrageenan in rat paws, and the compounds have also been shown to have an inhibitory effect on passive cutaneous anaphylaxis induced by injection of antigen (egg albumin) in rats.

Den typiske og markerte antiarhytmiske virkning er påvist i forbindelse med elektrisk, indusert hjerte-forkammerfibrillering og hjerteslag-takt og i forbindelse med arhytmi og opphør av hjerteslag indusert ved intravenøs tilførsel av lanastosid C. Disse fordelaktige virkninger oppnås ved doser som bare innebærer mindre bivirkninger og som ikke innebærer forgiftningsfare for pasienter. The typical and marked antiarrhythmic effect has been demonstrated in connection with electrically induced cardiac atrial fibrillation and heartbeat rhythm and in connection with arrhythmia and cessation of heartbeat induced by intravenous administration of lanastoside C. These beneficial effects are achieved at doses that involve only minor side effects and which does not entail a risk of poisoning for patients.

De ved fremgangsmåten i henhold til oppfinnelsen fremstillbare N-substituerte og N,N-disubstituerte aminokarbonylalkylforbindelser representeres som nevnt ved formelen I The N-substituted and N,N-disubstituted aminocarbonylalkyl compounds that can be prepared by the method according to the invention are represented as mentioned by the formula I

1 2 3' hvori R , Z, A, R og R har de angitte betydninger, og kan som nevnt fremstilles fra den tilsvarende nitrogenholdige heterocykliske forbindelse med formel II hvori Z og R<1> har den ovenfor angitte betydning henholdsvis fra den tilsvarende karboksylalkyl-forbindelse med formel III 1 2 3' in which R , Z, A, R and R have the indicated meanings, and can, as mentioned, be prepared from the corresponding nitrogen-containing heterocyclic compound of formula II in which Z and R<1> have the above-mentioned meaning respectively from the corresponding carboxylalkyl -compound of formula III

, hvori Z, A og R"<*>" har den ovenfor angitte betydning. , wherein Z, A and R"<*>" have the above meaning.

Når utgangsforbindelsen er forbindelsen med formel II underkastes denne en N-substituert eller N,N-disubstituert aminokarbonylalkylering. Den N-substituerte eller N,N-disubstituerte aminokarbonylalkylering kan gjennomføres ved å omsette forbindelsen med formel II (J. Pharm. Soc. Japan, 77, 347(1957)) eller dens reaktive derivat med et alkylhalogenid med den generelle formel When the starting compound is the compound of formula II, this is subjected to N-substituted or N,N-disubstituted aminocarbonyl alkylation. The N-substituted or N,N-disubstituted aminocarbonyl alkylation can be carried out by reacting the compound of formula II (J. Pharm. Soc. Japan, 77, 347(1957)) or its reactive derivative with an alkyl halide of the general formula

hvori X er halogen (f.eks. klor, brom, etc.) og A, R 2 og R 3 har den ovenfor angitte betydning. Eksempler på reaktive derivater av forbindelsen med formel II er metallsalter (natriumsaltet, kaliumsaltet, kalsiumsaltet, etc). Omsetningen gjennomføres vanlig i et inert løsningsmiddel som f.eks. benzen, toluen, eter, metanol, etanol, dimetylf ormamid, etc). Når forbindelsen med formel II anvendes som sådan er det ønskelig å anvende et in which X is halogen (e.g. chlorine, bromine, etc.) and A, R 2 and R 3 have the meaning given above. Examples of reactive derivatives of the compound of formula II are metal salts (the sodium salt, the potassium salt, the calcium salt, etc.). The reaction is usually carried out in an inert solvent such as e.g. benzene, toluene, ether, methanol, ethanol, dimethylformamide, etc). When the compound of formula II is used as such, it is desirable to use a

kondenseringsmiddel og sorn eksempler nevnes alkalihydroksyd (f .eks. natriumhydroksyd, kal iumhydroksyd, etc), alkal ikarbonat (f.eks. natriumkarbonat, kaliumkarbonat, etc), alkali-alkoksyd (f.eks. natriummetoksyd, natriumetoksyd, kaliumetoksyd, etc), alkalihydrid (f. eks. natriumhydrid, kal iumhydrid, etc), alkaliamid (f.eks. natriumamid, kaliumamid, litiumamid, etc.) og lignende. condensing agent and other examples are alkali hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc), alkali carbonate (e.g. sodium carbonate, potassium carbonate, etc), alkali alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium ethoxide, etc), alkali hydride (e.g. sodium hydride, potassium hydride, etc.), alkali amide (e.g. sodium amide, potassium amide, lithium amide, etc.) and the like.

Når utgangsforbindelsen er forbindelsen med formel III underkastes denne en N-substituert eller N,N-disubstituert aminering. Den N-substituerte eller N,N-disubstituerte aminering kan gjennomføres ved å omsette forbindelsen med formel III (britisk patentskrift nr. 862.226), dens salt eller dens reaktive derivat med et amin med den generelle formel When the starting compound is the compound of formula III, this is subjected to an N-substituted or N,N-disubstituted amination. The N-substituted or N,N-disubstituted amination can be carried out by reacting the compound of formula III (British Patent No. 862,226), its salt or its reactive derivative with an amine of the general formula

hvori R 2 og R 3 har den ovenfor angitte betydning. Eksempler på salter av forbindelsen med formel III er metallsalter (f.eks. natriumsalt, kaliumsalt, kalsiumsalt, etc), ammoniumsal ter, salter med organiske baser (f.eks. trietyl aminsal tet, ete.) og lignende. Eksempler på reaktive derivater av forbindelsen med formel III er in which R 2 and R 3 have the meaning stated above. Examples of salts of the compound with formula III are metal salts (e.g. sodium salt, potassium salt, calcium salt, etc.), ammonium salts, salts with organic bases (e.g. triethylamine salt, ether) and the like. Examples of reactive derivatives of the compound of formula III are

syrehalogenider (f.eks. syreklorid, syrebromid, etc), syreanhydrider (f.eks. alkylfosforsyreanhydrid, dibenzylfosforsyreanhydrid, halogen-fosforsyreanhydrid, dialkylfosforsyreanhydrid, svovel syriinganhydrid, "tiosvovelsyreanhydrid,.svovelsyreanhydrid, alkylkarbonsyreanhydrid, acid halides (e.g. acid chloride, acid bromide, etc), acid anhydrides (e.g. alkyl phosphoric anhydride, dibenzyl phosphoric anhydride, halo-phosphoric anhydride, dialkyl phosphoric anhydride, sulfuric acid anhydride, "thiosulfuric anhydride,.sulfuric anhydride, alkyl carbonic anhydride,

alifatisk karboksylsyreanhydrid, aromatisk karboksylsyreanhydrid, symmetrisk syreanhydrid, etc), syreamider (f.eks. syreamidet med imidazol, syreamidet med 4-substituer t imidazol, etc), syreestere (f.eks. metyl esteren, etylesteren, cyanometylesteren, p-nitro-fenylesteren. pentaklorfenylesteren, 2,4,5-triklorfenylesteren, propargylesteren, karboksymetyltioesteren, pyranylesteren, metoksy-metylesteren, fenyltioesteren, etc.) og syreazidet. Når forbindelsen med formel III anvendes som sådan er det vanlig nødvendig å anvende et kondenseringsmidd^el. Eksempler på kondenseringsmiddel er N,N'-dicykloheksylkarbodiimid, N-cykloheksyl-N1-morfol inoetyl-karbodiimid, N-cykloheksyl-N'-(4-dietyl-aminocykloheksyl)karbodiimid, aliphatic carboxylic acid anhydride, aromatic carboxylic anhydride, symmetrical acid anhydride, etc), acid amides (e.g. the acid amide with imidazole, the acid amide with 4-substituer t imidazole, etc), acid esters (e.g. the methyl ester, the ethyl ester, the cyanomethyl ester, p-nitro- the phenyl ester, the pentachlorophenyl ester, the 2,4,5-trichlorophenyl ester, the propargyl ester, the carboxymethylthioester, the pyranyl ester, the methoxymethylester, the phenylthioester, etc.) and the acid azide. When the compound of formula III is used as such, it is usually necessary to use a condensing agent. Examples of condensing agents are N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N1-morphoyl inoethylcarbodiimide, N-cyclohexyl-N'-(4-diethyl-aminocyclohexyl)carbodiimide,

N ,N' -dietyl-karbodiimid , N, N' -diisopropylkarbodiiraid, N-etyl-N1 - N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiiride, N-ethyl-N1 -

(3-dimetylaminopropyl)-karbodiimid, N,N<1->karbonyldi(2-metylimidazol), pentametyl enketen-N-cykloheksylimin, difenylketen-N-cykloheksylimin, alkoksyacetylen, 1-alkoksy-l-kloretylen, tetraalkylfosfit, N-etyl-O-fenylisoksazolium-3'-sulfonat, ety1polyfosf at, isopropylpolyfosfat, fosforoksyklorid, fosfortriklorid, tionylklorid, oksalylklorid, trifenylfosfin, etc. Omsetningen gjennomføres vanlig i et inert løsningsmiddel (f.eks. aceton, dioksan, acetonitril, kloroform, etylendiklorid, tetrahydrof uran, etylacetat, pyridin, etc). (3-dimethylaminopropyl)-carbodiimide, N,N<1->carbonyldi(2-methylimidazole), pentamethyl enketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, Alkoxyacetylene, 1-Alkoxy-1-chloroethylene, tetraalkylphosphite, N-ethyl -O-phenylisoxazolium-3'-sulfonate, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, etc. The reaction is usually carried out in an inert solvent (e.g. acetone, dioxane, acetonitrile, chloroform, ethylene dichloride, tetrahydrofuran uranium, ethyl acetate, pyridine, etc).

Om nødvendig kan en basisk substans (f.eks. alkalikarbonat, alkalihydrogenkarbonat, trialkylamin, pyridin, etc.) være tilstede under omsetningen. If necessary, a basic substance (e.g. alkali carbonate, alkali hydrogen carbonate, trialkylamine, pyridine, etc.) may be present during the reaction.

Noen av forbindelsene med formel I kan om ønsket fremstilles fra forbindelsene fremstilt ved den ene eller den annen av de nevnte to fundamentale fremgangsmåter (dvs. N-substituert eller N,N-disubstituert aminokarbonylalkylering henholdsvis N-substituert eller 'N,N-disubstituert aminering). Et eksempel på slike alternative fremgangsmåter er vist i det følgende reaksjonsskjerna: Some of the compounds of formula I can, if desired, be prepared from the compounds prepared by one or the other of the aforementioned two fundamental methods (ie N-substituted or N,N-disubstituted aminocarbonyl alkylation, respectively N-substituted or 'N,N-disubstituted amination ). An example of such alternative methods is shown in the following reaction core:

hvori X<1> er halogen (f.eks. klor, brom, etc.) og Z, A, R<1>, R4 og R~* har den ovenfor angitte betydning. wherein X<1> is halogen (e.g. chlorine, bromine, etc.) and Z, A, R<1>, R4 and R~* have the meaning given above.

I det ovenstående reaksjonsskjerna oppnås utgangsforbindelsen med formel Ia ved omsetning av forbindelsen med formel III med aziridin, som er en utførelsesform av den nevnte N,N-disubstituerte aminering. Omdannelsen av forbindelsen med formel Ia til forbindelsen med formel Ib kan utføres ved behandling av den førstnevnte med en halogenhydrogensyre (f.eks. saltsyre, bromhydrogensyre, jodhydrogen-syre, etc). Denne omdannelse finner imidlertid noen ganger sted etter fremstillingen av forbindelsen med formel Ia fra forbindelsen med formel III når en halogenhydrogensyre er tilstede. In the above reaction core, the starting compound of formula Ia is obtained by reacting the compound of formula III with aziridine, which is an embodiment of the aforementioned N,N-disubstituted amination. The conversion of the compound of formula Ia to the compound of formula Ib can be carried out by treating the former with a hydrohalic acid (eg hydrochloric acid, hydrobromic acid, hydroiodic acid, etc). However, this conversion sometimes takes place after the preparation of the compound of formula Ia from the compound of formula III when a hydrohalic acid is present.

Forbindelsen med formel Ib oppnådd på denne måte kan omsettes med et amin med formel The compound of formula Ib obtained in this way can be reacted with an amine of formula

hvori R 4 og R 5 hver har den tidligere angitte betydning, normalt i nærvær av en base (f.eks. natriumhydroksyd, kaliumhydroksyd, natriumkarbonat, natriumetoksyd, etc) til å gi f orbindel sen ' med formel Ic, som kan også fremstilles direkte fra forbindelsen med formel Ia ved å omsette denne med det nevnte amin. wherein R 4 and R 5 each have the previously indicated meaning, normally in the presence of a base (eg sodium hydroxide, potassium hydroxide, sodium carbonate, sodium ethoxide, etc) to give the compound of formula Ic, which can also be prepared directly from the compound of formula Ia by reacting this with the aforementioned amine.

Et annet eksempel på de alternative fremgangsmåter er vist i følgende "reaksjonssk jerna: Another example of the alternative methods is shown in the following "reaction diagram:

hvori X'• er halogen (f.eks. klor, brom, etc.) og Z, A, A<1>, R<1>, wherein X'• is halogen (e.g. chlorine, bromine, etc.) and Z, A, A<1>, R<1>,

2 4 5 2 4 5

R , R og R har den tidligere angitte betydning. R , R and R have the previously indicated meaning.

I det ovenstående reaksjonsskjerna oppnås utgangsforbindelsen med formel Id ved omsetning av forbindelsen med formel III med et amin med formel In the above reaction core, the starting compound of formula Id is obtained by reacting the compound of formula III with an amine of formula

hvori A<1> og R 2 har den tidligere angitte betydning, som er en utførelsesform av den nevnte N-substituerte eller N,N-disubstituerte aminering. Omdannelse,n av forbindelsen med formel Id til forbindelsen med formel le kan utføres ved å halogenere den først-nevnte med et halogeneringsmiddel ved en i og for seg vanlig kjent metode. Den påfølgende omdannelse av forbindelsen med formel le til forbindelsen med formel If kan utføres ved å omsette den førstnevnte med et amin med formel wherein A<1> and R 2 have the previously indicated meaning, which is an embodiment of the aforementioned N-substituted or N,N-disubstituted amination. Conversion of the compound of formula Id to the compound of formula le can be carried out by halogenating the first-mentioned with a halogenating agent by a method commonly known per se. The subsequent conversion of the compound of formula le into the compound of formula If can be carried out by reacting the former with an amine of formula

hvori R 4 og R 5 hver har den tidligere angitte betydning, normalt i nærvær av en base (f.eks. natriumhydroksyd, kaliumhydroksyd, natriumkarbonat, natriumetoksyd, etc). wherein R 4 and R 5 are each as previously defined, normally in the presence of a base (eg sodium hydroxide, potassium hydroxide, sodium carbonate, sodium ethoxide, etc).

Et annet eksempel på de alternative fremgangsmåter er vist i følgende reaksjonsskjerna Another example of the alternative methods is shown in the following reaction core

hvori R er hydrogen eller lavere alkyl (f.eks. metyl, etyl, propyl, etc), R 7 og R 8 er hver hydrogen eller lavere alkyl (f.eks. metyl, etyl j propyl, etc.) og Z, A og R"1" har hver den tidligere angitte betydning. I ovenstående reaksjonsskjerna oppnås utgangsforbindelsen med formel lg ved omsetning av forbindelsen med formel III med et amin med formel hvori R 7 og R 8 har den tidligere angitte betydning, hvilket er en utførelsesform av den nevnte N,N-disubstituerte aminering. Omdannelsen av forbindelsen med formel lg til forbindelsen med formel Ih kan gjennomføres ved å omsette den førstnevnte med et alkylenoksyd med formel wherein R is hydrogen or lower alkyl (eg, methyl, ethyl, propyl, etc), R 7 and R 8 are each hydrogen or lower alkyl (eg, methyl, ethyl j propyl, etc.) and Z, A and R"1" each have the previously indicated meaning. In the above reaction core, the starting compound of formula Ig is obtained by reacting the compound of formula III with an amine of formula in which R 7 and R 8 have the previously indicated meaning, which is an embodiment of the aforementioned N,N-disubstituted amination. The conversion of the compound of formula Ig to the compound of formula Ih can be carried out by reacting the former with an alkylene oxide of formula

hvori R g .har den tidligere angitte betydning. Omsetningen kan gjennomføres i et inert løsningsmiddel (f.eks. metanol, etanol, aceton, kloroform, dioksan, benzen, n-heksan, toluen xylen, etc.). I stedet for det inerte løsningsmiddel kan selve alkylenoksydet (f.eks. etylenoksyd, propylenoksyd, etc.) tjene som reaksjonsmedium. wherein R g .has the previously stated meaning. The reaction can be carried out in an inert solvent (e.g. methanol, ethanol, acetone, chloroform, dioxane, benzene, n-hexane, toluene xylene, etc.). Instead of the inert solvent, the alkylene oxide itself (e.g. ethylene oxide, propylene oxide, etc.) can serve as the reaction medium.

Et annet eksempel på de alternative fremgangsmåter er vist i følgende reaks jonssk jerna,. hvori A<1>' er lavere alkylen (f.eks. metylen, etylen, metylmetylen, trimetylen, propylen, etc.) og Z, A, R 1, R 7 og R 8 hver har den ovennevnte betydning. Den ovenstående omdannelse av forbindelsen med formel lg til forbindelsen med formel li kan gjennomføres ved å omsette den førstnevnte med en halogenalkanol med formel Another example of the alternative methods is shown in the following reaks jonsk jerna,. wherein A<1>' is lower alkylene (eg, methylene, ethylene, methylmethylene, trimethylene, propylene, etc.) and Z, A, R 1 , R 7 and R 8 each have the above meaning. The above conversion of the compound of formula lg to the compound of formula li can be carried out by reacting the former with a haloalkanol of formula

hvori X''' er halogen (f.eks. klor, brom, jod, etc.) og A'' har den tidligere angitte betydning. Omsetningen kan gjennomføres i et inert løsningsmiddel (f.éks. metanol, etanol, eter, benzen, aceton, dimetylf ormamid, dimetyl sul f oksyd , etc), om nødvendig i nærvær av et kondenseringsmiddel som f.eks. alkalikarbonat (f.eks. natriumkarbonat, kaliumkarbonat, etc), jordalkalikarbonat wherein X''' is halogen (e.g. chlorine, bromine, iodine, etc.) and A'' has the previously indicated meaning. The reaction can be carried out in an inert solvent (e.g. methanol, ethanol, ether, benzene, acetone, dimethylformamide, dimethyl sulfoxide, etc.), if necessary in the presence of a condensing agent such as e.g. alkali carbonate (e.g. sodium carbonate, potassium carbonate, etc), alkaline earth carbonate

(f.eks. magnesiumkarbonat, kalsiumkarbonat, bariumkarbonat, etc.) (e.g. magnesium carbonate, calcium carbonate, barium carbonate, etc.)

eller alkalihydrogenkarbonat (f.eks. natriumhydrogenkarbonat, kalium-hydrogenkarbonat, etc.). I stedet for det inerte løsningsmiddel kan selve halogenalkanolen (f.eks. 2-brometanol, 2-kloretanol, 2-jodetanol, 3-brompropanol, l-brom-2-propanol, etc.) tjene som reaksjonsmedium. or alkali hydrogen carbonate (eg sodium hydrogen carbonate, potassium hydrogen carbonate, etc.). Instead of the inert solvent, the haloalkanol itself (e.g. 2-bromoethanol, 2-chloroethanol, 2-iodoethanol, 3-bromopropanol, 1-bromo-2-propanol, etc.) can serve as the reaction medium.

Et annet eksempel på de alternative fremgangsmåter er vist i følgende reaksjonsskjerna Another example of the alternative methods is shown in the following reaction core

den tidligere nevnte betydning, A'<11> er lavere alkylen (f.eks. metylen, etylen, metylmetylen, trimetylen, propylen), R er lavere alkanoyl (f.eks. acetyl, propionyl, butyryl) og Z, A og R har %hver den tidligere nevnte betydning. I det ovenstående reaksjonsskjerna oppnås utgangsforbindelsen med formel Ij ved omsetning av forbindelsen med formel II med et alkylhalogenid med formel hvori X, B, A og A''' hver har den tidligere nevnte betydning, hvilket er en utførelsesform av den nevnte N-substituerte eller N,N-disubstituerte aminokarbonylalkylering av forbindelsen med formel III med et amin med formel hvori B og A''<1> hver har den tidligere nevnte betydning, hvilket er en utførelsesform av den nevnte N-substituerte eller N,N-disubstituerte aminering. Forbindelser som faller innenfor kategorien av de nevnte forbindelser Ih eller li kan også anvendes som utgangsforbindelse ved denne fremgangsmåte. Omdannelsen av forbindelsen med formel Ij til forbindelsen med formel Ik kan gjennomføres ved å omsette den førstnevnte med et alkanoyleringsmiddel. Eksempler på alkanoyleringsmidler er lavere alkansyre-anhydrider (f.eks. eddiksyreanhydrid, propionsyreanhydrid, smørsyre-anhydrid) og lavere alkansyrehalogenider (f.eks. acetylklorid, acetylbromid, propionylklorid, butyrylklorid). Omsetningen kan gjennomføres ved i og for seg kjente metoder for alkanoylering. Et ytterligere eksempel på de alternative fremgangsmåter er vist i følgende reaksjonsskjerna hvori A''<*> er lavere alkylen og R"^ er lavere alkyl, med tilsammen høyst 6 karbonatomer (f.eks. metyl, etyl, propyl, isopropyl) og Z, B, A og R har den tidligere angitte betydning. I det ovenstående reaksjonsskjerna oppnås utgangsforbindelsen med formel Im ved omsetning av forbindelsen med formel II med et alkylhalogenid med formel hvori X, B, A, A<1>'' og R1(^ hver har den tidligere angitte betydning, hvilket er en utf ørelsesf orm av den nevnte N-substituerte eller N,N-disubstituerte aminokarbonylalkylering av forbindelsen med formel III med et amin med formel hvori B, A''<1> og R"^ hver har den ovennevnte betydning, hvilket er en utførelsesform av den nevnte N-substituerte eller N,N-disubstituerte aminering. Omdannelsen av forbindelsen med formel Im til forbindelsen med formel In kan gjennomføres ved å behandle den førstnevnte med et reduseringsmiddel, fortrinnsvis alkali-metallhydridkompleks (f.eks. litiumaluminiumhydrid) i et inert løsningsmiddel (f.eks. eter, tetrahydrofuran, dioksan). Ennå et eksempel på de alternative fremgangsmåter er vist i følgende reaksjonsskjerna hvori R<11> er lavere alkyl (f.eks. metyl, etyl, propyl, isopropyl) og Z, B, A, A''' og R"*" har den tidligere angitte betydning. I det ovenstående reaksjonsskjerna oppnås utgangsforbindelsen med formel Io ved omsetning av forbindelsen med formel II med et alkylhalogenid med formelen, hvori X, B, A, A'<*>' og R<11> har den tidligere angitte betydning, hvilket er en utførelsesform av den nevnte N-substituerte eller N,N-disubstituerte aminokarbonylalkylering, eller ved omsetning av forbindelsen med formel III med et amin med formelen the aforementioned meaning, A'<11> is lower alkylene (eg methylene, ethylene, methylmethylene, trimethylene, propylene), R is lower alkanoyl (eg acetyl, propionyl, butyryl) and Z, A and R has %every the previously mentioned meaning. In the above reaction core, the starting compound of formula Ij is obtained by reacting the compound of formula II with an alkyl halide of formula wherein X, B, A and A''' each have the previously mentioned meaning, which is an embodiment of the aforementioned N-substituted or N,N-disubstituted aminocarbonyl alkylation of the compound of formula III with an amine of formula wherein B and A''<1> each have the previously mentioned meaning, which is an embodiment of said N-substituted or N,N-disubstituted amination. Compounds that fall within the category of the aforementioned compounds Ih or li can also be used as starting compound in this method. The conversion of the compound of formula Ij to the compound of formula Ik can be carried out by reacting the former with an alkanoylating agent. Examples of alkanoylating agents are lower alkanoic acid anhydrides (e.g. acetic anhydride, propionic anhydride, butyric anhydride) and lower alkanoic acid halides (e.g. acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride). The conversion can be carried out by methods known per se for alkanoylation. A further example of the alternative methods is shown in the following reaction core in which A''<*> is lower alkylene and R"^ is lower alkyl, with a total of at most 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl) and Z . each has the previously stated meaning, which is an embodiment of said N-substituted or N,N-disubstituted aminocarbonyl alkylation of the compound of formula III with an amine of formula wherein B, A''<1> and R"^ each has the above-mentioned meaning, which is an embodiment of the aforementioned N-substituted or N,N-disubstituted amination.The conversion of the compound of formula Im to the compound of formula In can be carried out by treating the former with a reducing agent, preferably an alkali metal hydride complex e.g. (e.g. lithium aluminum hydride) in an inert solvent (eg ether, tetrahydrofuran, dioxane). Yet another example of the alternative methods is shown in the following reaction core in which R<11> is lower alkyl (e.g. methyl, ethyl, propyl, isopropyl) and Z, B, A, A''' and R"*" have the previously stated meaning. In the above reaction core, the starting compound of formula Io is obtained by reacting the compound of formula II with an alkyl halide of the formula, in which X, B, A, A'<*>' and R<11> have the previously indicated meaning, which is an embodiment of the aforementioned N-substituted or N,N-disubstituted aminocarbonyl alkylation, or by reacting the compound of formula III with an amine of the formula

hvori B, A'<*>' og R har den tidligere angitte betydning, hvilket er en utførelsesform av den nevnte N-substituerte eller N,N-disubstituerte aminering. Omdannelsen av forbindelsen med formel Io til forbindelsen med formel lp kan utføres ved å behandle den førstnevnte med et reduksjonsmiddel, fortrinnsvis alkalimetall-hydridkompleks (f.eks. 1itiumaluminiumhydrid) i et inert løsnings-middel (f.eks. eter, tetrahydrofuran, dioksan). wherein B, A'<*>' and R have the previously indicated meaning, which is an embodiment of the aforementioned N-substituted or N,N-disubstituted amination. The conversion of the compound of formula Io to the compound of formula 1p can be carried out by treating the former with a reducing agent, preferably an alkali metal hydride complex (e.g. lithium aluminum hydride) in an inert solvent (e.g. ether, tetrahydrofuran, dioxane) .

Forbindelsene med formel I har generelt og karakteristisk anti-inf 1 ammatorisk og/eller antiarhytmisk aktivitet. Blant disse viser følgende forbindelser relativt høy antiinflammatorisk potens: 3-/24"-(2-hydroksyetyl )-l-piperazinylkarbonyImetyl/-5-klor-2(3H) - benzotiazolinon, N-(2-hydroksypropyl)-5-klor-2-okso-3-benzo— tiazolin-acetamid, N-(2-hydroksyetyl)-6-klor-2-okso-3-benzotiazolin-acetamid, N-2-(2-hydroksyetoksy)etyl-5-klor-2-okso-3-benzotiazolin-acetamid ,N-(2-etoksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid, N-metyl-5-trifluormetyl-2-okso-3-benzotiazolinacetamid. Følgende forbindelser viser videre relativt sterk antiarhytmisk potens: N-2-(N,N-dietylamino)-etyl-2-okso-3-benzotiazolinacetamid, N-2-(N,N-dietylamino)etyl-5-klor-2-okso-3-benzotiazolinacetamid, N-3-(N,N-dimetylamino)propyl-2-okso-3-benzotiazolin-acetamid, N-2-(N,N-dietylamino)etyl-6-etoksy-2-okso-3-benzotiazolinacetamid. The compounds of formula I generally and characteristically have anti-inflammatory and/or antiarrhythmic activity. Among these, the following compounds show relatively high anti-inflammatory potency: 3-[24"-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone, N-(2-hydroxypropyl)-5-chloro- 2-oxo-3-benzothiazoline-acetamide, N-(2-hydroxyethyl)-6-chloro-2-oxo-3-benzothiazoline-acetamide, N-2-(2-hydroxyethoxy)ethyl-5-chloro-2 -oxo-3-benzothiazoline-acetamide ,N-(2-ethoxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide, N-methyl-5-trifluoromethyl-2-oxo-3-benzothiazolineacetamide The following compounds further show relatively strong antiarrhythmic potency: N-2-(N,N-diethylamino)-ethyl-2-oxo-3-benzothiazolineacetamide, N-2-(N,N-diethylamino)ethyl-5-chloro-2-oxo-3-benzothiazolineacetamide , N-3-(N,N-dimethylamino)propyl-2-oxo-3-benzothiazoline-acetamide, N-2-(N,N-diethylamino)ethyl-6-ethoxy-2-oxo-3-benzothiazolineacetamide.

Forbindelsene med formel I kan følgelig anvendes ved behandling av inflammatoriske tilstander forbundet med smerte, betennelser og/eller hevelser frembragt ved endringer i cellulær og vaskulær permeabilitet, The compounds of formula I can consequently be used in the treatment of inflammatory conditions associated with pain, inflammation and/or swelling produced by changes in cellular and vascular permeability,

vasodilatering, eksudering av flytende bestanddeler i blodet og vasodilatation, exudation of liquid components in the blood and

cellebestanddeler og/eller hyppig dannelse av bindevev-celler og dannelse av granulasjonsvev. Forbindelsene med formel I er også brukbare for behandling av visse arhytmier. Omdannelse av atrial fibrilering, opphevelse av paroksysmal atrial tachycardia, og styring av ventrikulære ektopiske slag representerer typiske eksempler på terapeutiske anvendelser. cell constituents and/or frequent formation of connective tissue cells and formation of granulation tissue. The compounds of formula I are also useful for the treatment of certain arrhythmias. Reversal of atrial fibrillation, reversal of paroxysmal atrial tachycardia, and management of ventricular ectopic beats represent typical examples of therapeutic applications.

Forbindelsene med formel I kan tilføres på vanlig måte med vanlige typer av enhetsdoser eller med vanlige farmasøytiske bærere for å frembringe en antiinflammatorisk eller antiarrytmisk effekt i dyr og mennesker. De kan således anvendes i form av farmasøytiske preparater som inneholder forbindelsene i blanding med farmasøytiske organiske eller uorganiske bærermaterialer egnet for enteral, parenteral eller lokal tilførsel. Oral tilførsel ved hjelp av tabletter, kapsler eller i flytende form som suspensjoner, oppløsninger eller emulsjoner er særlig fordelaktig. Når forbindelsene tilføres i tablettform kan de vanlige binde- og opp-løsningsfremmende midler som vanlig anvendt i terapeutiske enhetsdoser anvendes. Som eksempler på bindemidler kan nevnes glukose, laktose, gum acacia, gelatin, mannitol, stivelsespasta, magnesiumtrisilikat og talkum. Som eksempler på oppløsningsfremmende midler kan nevnes kornstivelse, keratin, kolloidal silika og potetstivelse. Når forbindelsene tilføres som væske kan de vanlige flytende bærere anvendes. The compounds of formula I can be administered in a conventional manner with conventional types of unit doses or with conventional pharmaceutical carriers to produce an anti-inflammatory or antiarrhythmic effect in animals and humans. They can thus be used in the form of pharmaceutical preparations containing the compounds in admixture with pharmaceutical organic or inorganic carrier materials suitable for enteral, parenteral or local administration. Oral administration by means of tablets, capsules or in liquid form such as suspensions, solutions or emulsions is particularly advantageous. When the compounds are supplied in tablet form, the usual binding and dissolution-promoting agents commonly used in therapeutic unit doses can be used. Examples of binders include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate and talc. Examples of dissolution promoting agents include corn starch, keratin, colloidal silica and potato starch. When the compounds are supplied as liquid, the usual liquid carriers can be used.

Enhetsdosen for terapeutisk effektive mengder av forbindelsene med formel I for mennesker kan variere innen vide grenser som fra 5 mg til lg, idet den øvre grense bare bestemmes ved graden av ønsket virkning og økonomiske betraktninger. For oral tilførsel foretrekkes det å anvende fra 50 til 500 mg av den terapeutiske forbindelse pr. enhetsdose. Ved dyreforsøk er det påvist at fra omtrent 5 til 50 mg doser tilført oralt fire ganger daglig etter behov vil gi en foretrukket daglig dose. Doseringen av den spesielle terapeutiske forbindelse kan variere betraktelig, f.eks. The unit dose for therapeutically effective amounts of the compounds of formula I for humans may vary within wide limits such as from 5 mg to 1g, the upper limit being determined only by the degree of desired effect and economic considerations. For oral administration, it is preferred to use from 50 to 500 mg of the therapeutic compound per unit dose. In animal experiments, it has been shown that from approximately 5 to 50 mg doses given orally four times a day as needed will give a preferred daily dose. The dosage of the particular therapeutic compound may vary considerably, e.g.

i avhengighet av pasientens alder og graden av terapeutisk effekt 'som ønskes. Hver enhetsdose av de nye terapeutiske forbindelser kan inneholde fra 5 til 95 vektprosent av den nye terapeutiske forbindelse regnet på hele blandingen idet resten omfatter vanlige farmasøytiske bærere. Betegnelsen farmasøytisk bærer er ment å inkludere ikke-terapeutiske materialer som vanlig anvendes med enhetsdoser og omfatter fyllstoffer, forsyningsmidler, bindemidler, smøremidler, oppløsningsfremmende midler og løsningsmidler. Det er selvfølgelig mulig å tilføre de nye terapeutiske forbindelser som rene forbindelser uten bruk av noen farmasøytisk bærer. depending on the patient's age and the degree of therapeutic effect 'desired. Each unit dose of the new therapeutic compounds may contain from 5 to 95 percent by weight of the new therapeutic compound calculated on the entire mixture, the remainder comprising common pharmaceutical carriers. The term pharmaceutical carrier is intended to include non-therapeutic materials commonly used with unit doses and includes fillers, excipients, binders, lubricants, solubilizers and solvents. It is of course possible to add the new therapeutic compounds as pure compounds without the use of any pharmaceutical carrier.

Praktiske og i dag foretrukne utførelsesformer for fremgangsmåten Practical and currently preferred embodiments of the method

i henhold til oppfinnelsen er illustrert i de følgende utførelses-eksempler. according to the invention is illustrated in the following embodiment examples.

Eksempel 1 Example 1

En blanding av 5-klor-2(3H)-benzotiazolinon (5.0 g), 4'-hydroksy-2-kloracetanilid (5.54 g), kaliumkarbonat (3.75 g) og aceton (20 ml) oppvarmes under tilbakeløp i 6 timer. Reaksjonsblåndingen filtreres mens den er varm. Filtratet konsentreres til tørrhet. Resten krystalliseres fra etylacetat og gir 4'-hydroksy-5-klor-2-okso-3-benzotiazolinacetanilid (4,2 g) som krystaller med smeltepunkt 249 - 251°C. A mixture of 5-chloro-2(3H)-benzothiazolinone (5.0 g), 4'-hydroxy-2-chloroacetanilide (5.54 g), potassium carbonate (3.75 g) and acetone (20 ml) is heated under reflux for 6 hours. The reaction mixture is filtered while it is hot. The filtrate is concentrated to dryness. The residue is crystallized from ethyl acetate and gives 4'-hydroxy-5-chloro-2-oxo-3-benzothiazolineacetanilide (4.2 g) as crystals with a melting point of 249 - 251°C.

Andre eksempler på forbindelser som kan fremstilles på lignende måte omfatter: 3-/4-(2-hydroksyetyl)-1-piperazinylkarbonylmetyl7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 159 til 161°C), Other examples of compounds which can be prepared in a similar manner include: 3-(4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl-7-5-chloro-2(3H)-benzothiazolinone (m.p. 159 to 161°C),

3-(4-hydroksypiperidinokarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 178 til 181°C), 3-(4-hydroxypiperidinocarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (melting point 178 to 181°C),

N-^2~-(N, N-dietyl amino) etyj/7-2-okso-3-benzotiazol inacetamid (maleatet har smeltepunkt 138.5 til 139.5°C), N-^2~-(N,N-diethyl amino)ethyj/7-2-oxo-3-benzothiazole inacetamide (the maleate has a melting point of 138.5 to 139.5°C),

3-/4\-(2-hydroksyetyl)-1-piper azinylkarbonylmetyl_7-2 ( 3H)-benzot~iazolinon (maleatet har smeltepunkt 197 til 198°C, 3-(4-metyl-l-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 178 til 179°C), 3-/4\-(2-Hydroxyethyl)-1-piper azinylcarbonylmethyl_7-2 ( 3H)-benzothiazolinone (the maleate has a melting point of 197 to 198°C, 3-(4-methyl-1-piperazinylcarbonylmethyl)-5-chloro -2(3H)-benzothiazolinone (melting point 178 to 179°C),

3-(4-metyl-l-piperazinylkarbonylmetyl)-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 193 til 195°C), 3-(4-methyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (melting point 193 to 195°C),

3-^4-( 2-hydroksyetyl) -1-piperazinylkarbonylmetyl_/-5-trif luormetyl-2(3H)-benzotiazolinon (smeltepunkt 166 til 167.5°C), N-(2-hydroksyetyl)-6-klor-2-okso-3-benzotiazolinacetamid (smeltepunkt 222 til 223°C), 3-^4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl_/-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 166 to 167.5°C), N-(2-hydroxyethyl)-6-chloro-2- oxo-3-benzothiazolineacetamide (melting point 222 to 223°C),

N-metyl-5-trifluormetyl-2-okso-3-benzotiazolinacetamid N-methyl-5-trifluoromethyl-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 223 til 224°C), (melting point 223 to 224°C),

3-(4-acetyImetyl-1-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 158 til 160°C), 3-(4-acetylmethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (melting point 158 to 160°C),

3-/2 ,5-dimetyl-4-(1-etoksykarbonylmetyl)-1-piperaziny1karbonyl-metyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 131 til 138°C), 3-(2,5-dimethyl-4-(1-ethoxycarbonylmethyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (melting point 131 to 138°C),

3-/2 , 5-dimetyl-4-( 2-hydroksyetyl) -l-piperazinylkarbonylmetyl7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 139 til 141°C), 3//4-( 2-hydroksyetyl) -1-piper azi ny lkarbonyjy-l-etyl_"7-5-klor-benzotiazolinon (smeltepunkt 89 til 92°C), 1 -/4-(2-hy dr ok sye tyl) -1-piper azinylkarbonyl me ty_l/-3-metyl-6-klor-2(3H)-benzimidazolinon (smeltepunkt 172 til 174°C), 1-/4-(2-hydroksyetyl)-1-piperazinylkarbonyImetyl/-3-metyl-5-klor-2(3H)-benzimidazolinon (smeltepunkt 171 til 173°C), l-/_4-( 2-hydr ok sy propyl) -1-piper azi nyl karbonyl metyl7-3-me tyl-6-klor-2(3H)-benzoimidazolinon (smeltepunkt 202 til 206°C), 3-/5 -( 2-hydroksypropyl) -1-piper azi ny 1 karbonyl me tyl_7-5-k lor-2 ( 3H) - benzotiazolinon (smeltepunkt 104 til 105°C), såvel som følgende forbindelser: 3-/4-(2-hydr ok sye ty 1)-1-piper azi nyl karbonyl me ty_l7-6-e tok sy-2( 3H)-benzotiazolinon (smeltepunkt 154 til155°C) 3-/2,5-Dimethyl-4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl7-5-chloro-2(3H)-benzothiazolinone (m.p. 139 to 141°C), 3//4-(2-Hydroxyethyl) -1-piper azinylcarbonyl-1-ethyl_"7-5-chloro-benzothiazolinone (m.p. 89 to 92°C), 1-/4-(2-hydroxyethyl)-1-piper azinylcarbonyl methyl_l/ -3-methyl-6-chloro-2(3H)-benzimidazolinone (m.p. 172 to 174°C), 1-(4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl)-3-methyl-5-chloro-2( 3H)-benzimidazolinone (m.p. 171 to 173°C), 1-/_4-(2-hydroxy propyl)-1-piperazinyl carbonyl methyl7-3-methyl-6-chloro-2(3H)-benzoimidazolinone (melting point 202 to 206°C), 3-/5-(2-hydroxypropyl)-1-piperaziny 1 carbonyl methyl_7-5-chlor-2 ( 3H)-benzothiazolinone (melting point 104 to 105°C), as well as the following compounds: 3-[4-(2-hydroxy cy ty 1)-1-piper azinyl carbonyl methyl 17-6-e toc sy-2(3H)-benzothiazolinone (m.p. 154 to 155°C)

N-/2-(N,N-dietylamino)ety^/-5-klor-2-okso-3-benzotiazolinacetamid N-(2-(N,N-diethylamino)ethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 127 til 128°C; maleatet har smeltepunkt 119 til 121°C) (melting point 127 to 128°C; the maleate has melting point 119 to 121°C)

N-/3-(N,N-dimetylamino)propyl/-2-okso-3-benzotiazolinacetamid N-[3-(N,N-dimethylamino)propyl]-2-oxo-3-benzothiazolineacetamide

(maleatet har smeltepunkt 155 til 156°C) (the maleate has a melting point of 155 to 156°C)

N-/2-(N,N-dietylamino)etylV-6-metyl-2-okso-3-benzotiazolinacetamid N-(2-(N,N-diethylamino)ethyl N-6-methyl-2-oxo-3-benzothiazolineacetamide

(maleatet har smeltepunkt'113 til 114°C) (the maleate has a melting point of 113 to 114°C)

N-/2-(N, N-dietyl ami no) ety_l7-6-etoksy-2-okso-3-benzo ti azol inacetamid N-(2-(N,N-diethylamino)ethyl-17-6-ethoxy-2-oxo-3-benzothiazole inacetamide

(smeltepunkt 131°C) (melting point 131°C)

3-/4-(2-hydroksyetyl )-l-pi per azi nyl karbonyl me tyl/-6-klor-2 (3H)-benzotiazolinon (smeltepunkt 175 til 177°C) 3-(4-(2-Hydroxyethyl)-1-piperazinyl carbonyl methyl)-6-chloro-2(3H)-benzothiazolinone (m.p. 175 to 177°C)

3-/4-(2-hydroksyetyl)-1-piper azi ny lkarbonyl me tyV-4-klor-2 (3H)-benzotiazolinon (smeltepunkt 189 til 191°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl)-4-chloro-2(3H)-benzothiazolinone (m.p. 189 to 191°C)

3-(4-hydroksypiperidinokarbonylmetyl)-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 197 til 199°C) 3-(4-hydroxypiperidinocarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 197 to 199°C)

N-/2-(2-hydr ok sye tok sy) etyl/-5-klor-2-okso-3-benzo ti azol inacetamid N-/2-(2-Hydr ok sye tok sye) ethyl/-5-chloro-2-oxo-3-benzo thiazole inacetamide

(smeltepunkt 133 til 134°C) (melting point 133 to 134°C)

N,N-dietyl-5-klor-2-okso-3-benzotiazolinacetamid (smeltepunkt N,N-diethyl-5-chloro-2-oxo-3-benzothiazolineacetamide (melting point

148 til 149°C)' 148 to 149°C)'

N-(2-hydroksypropyl)-7-klor-2-okso-3-benzotiazolinacetami d N-(2-hydroxypropyl)-7-chloro-2-oxo-3-benzothiazolineacetami d

(smeltepunkt 189 til 191°C) (melting point 189 to 191°C)

N-(2-hydroksypropyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 155 til 156°C) (melting point 155 to 156°C)

N-(2-hydroksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid (smeltepunkt 223 til 224°C, N-(2-Hydroxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (m.p. 223 to 224°C,

N-metyl-N-(2-hydroksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid N-methyl-N-(2-hydroxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 115 til 117°C) (melting point 115 to 117°C)

3-(1-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon 3-(1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone

(smeltepunkt 211 til 212°C) (melting point 211 to 212°C)

N-(2-etoksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-ethoxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 171 til 173°C) (melting point 171 to 173°C)

N-^2-(N,N-dicykloheksylamino)etyl/-5-klor-2-okso-3-benzotiazolin-acetamid (smeltepunkt 209 til 210°C N-^2-(N,N-dicyclohexylamino)ethyl/-5-chloro-2-oxo-3-benzothiazoline-acetamide (m.p. 209 to 210°C

N-(2-kloretyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-chloroethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 192 til 194°C) (melting point 192 to 194°C)

N-(2-k1orety1)-2-okso-3-benzotiazolinacetamid N-(2-chloroethyl)-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 159 til 162°C) (melting point 159 to 162°C)

3-/4-(2-hydroksypropyl)-1-piperazinylkarbonylmetyl/-5-klor-2(3H)— benzotiazolinon (smeltepunkt 112 til 115°C) 3-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 112 to 115°C)

3-/_"4-(2~hydroksybutyl)-1-piperazinylkarbonylmetyl/-5-klor-2 (3H)-benzotiazolinon (smeltepunkt 95 til 98°C) 3-/_"4-(2~Hydroxybutyl)-1-piperazinylcarbonylmethyl/-5-chloro-2(3H)-benzothiazolinone (melting point 95 to 98°C)

3-/4- (2-e tok syk arbonyl etyl)-1-piper azi nyl karbonyl metyl/-5-klor-2(3H)-benzotiazolinon (maleatet har smeltepunkt 152 til 154°C) 3-/4-(2-e tok syk carbonyl ethyl)-1-piper azinyl carbonyl methyl/-5-chloro-2(3H)-benzothiazolinone (the maleate has a melting point of 152 to 154°C)

3-/4-(3-hydroksypropyl)-l-piperazinylkarbonylmety_^/-5-klor-2(3H)-benzotiazolinon (sme ltepunkt 118 til 120 C) 3-(4-(3-Hydroxypropyl)-1-piperazinylcarbonylmethyl-5-chloro-2(3H)-benzothiazolinone (m.p. 118 to 120 C)

3-(2,4,5-trimetyl-l-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 167 til 173°C) 3-(2,4,5-trimethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 167 to 173°C)

3-/4-(2-acetoksyetyl) -1-piper azi nyl karbonyl me tyjL/-5-klor-2 (3H) - benzotiazolinon (maleatet har sme ltepunkt 199.5 til 200 Q) 3-[4-(2-acetoxyethyl)-1-piperazinyl carbonyl methyl]-5-chloro-2(3H)-benzothiazolinone (the maleate has a melting point of 199.5 to 200 °C)

3-/4-(2-isobutyryloksypropyl)-1-piperazinylkarbonyImetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 123 til 125°C) 3-(4-(2-isobutyryloxypropyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 123 to 125°C)

3-/4-(2-hydroksyetyl)-1-piperazinylkarbonylmetyl/-7-klor-2(3H)-benzotiazolinon (smeltepunkt 170 til 172°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl)-7-chloro-2(3H)-benzothiazolinone (melting point 170 to 172°C)

N-(2-hydroksypropyl)-6-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-6-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 167 til 173°C) (melting point 167 to 173°C)

3-(4-acetylmety1-1-piperazinylkarbonyImetyl)-5-trif1uormetyl-2(3H)-benzotiazolinon (smeltepunkt 170 til 172°C) 3-(4-acetylmethyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (melting point 170 to 172°C)

3-/4-(2-isobutyryloksyetyl) -1-<p>i<p>erazin<y>lkarbon<y>lmetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 111 til 113°C) 3-/4-(2-isobutyryloxyethyl)-1-<p>i<p>erazine<y>lcarbon<y>lmethyl/-5-chloro-2(3H)-benzothiazolinone (m.p. 111 to 113°C)

3-/4-(2-hydroksypropyl)-1-piperazinylkarbonyImety l7-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 152.5 til 154°C) 3-(4-(2-hydroxypropyl)-1-piperazinylcarbonylmethyl 7-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 152.5 to 154°C)

3-/4-(2-acetoksypropyl)-1-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (hydrokloridet har smeltepunkt 248 til 249°C) 3-/4-(2-acetoxypropyl)-1-piperazinylcarbonylmethyl/-5-chloro-2(3H)-benzothiazolinone (the hydrochloride has a melting point of 248 to 249°C)

N-(2-hydroksypropyl)-5-trifluormetyl-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-5-trifluoromethyl-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 154 til 155°C) (melting point 154 to 155°C)

N-(3-hydroksypropyl)-6-klor-2-okso-3-benzotiazolinacetamid N-(3-hydroxypropyl)-6-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 169 til 173°C) (melting point 169 to 173°C)

3-(2,5-dimetyl-1-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 285 til 288°C) 3-(2,5-dimethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 285 to 288°C)

3-/4-(l-etoksykarbonyletyl-1-piperazinylkarbonylmetylT/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 152 til 154°C) 3-(4-(1-ethoxycarbonylethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 152 to 154°C)

3-(1-piperazinylkarbonylmetyl)-5-trif1uormetyl-2(3H)-benzotiazolinon 3-(1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone

(smeltepunkt 163 til 165°C) (melting point 163 to 165°C)

3-/4- (1 -metyl-2-hydr ok sy ety 1)-1-piper aziny lkarbony Ime ty_l_7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 102 til 105°C) 3-(4-(1-Methyl-2-hydroxyethyl)-1-piperazinylcarbonyl)-7-5-chloro-2(3H)-benzothiazolinone (m.p. 102 to 105°C)

3-(4-metyl-1-piperazinylkarbonylmetyl)-2(3H)-benzotiazolinon 3-(4-methyl-1-piperazinylcarbonylmethyl)-2(3H)-benzothiazolinone

(smeltepunkt 155 til 156°C) (melting point 155 to 156°C)

U-/ 2-(N,N-dietylamino)etyl7-3-metyl-6-klor-2-okso-l-benzimidazolin-acetamid (smeltepunkt 124 til 125°C) U-/ 2-(N,N-diethylamino)ethyl7-3-methyl-6-chloro-2-oxo-1-benzimidazoline-acetamide (melting point 124 to 125°C)

N-/ 2-(N,N-dietylamino)etyl/-5-trifluormetyl-2-okso-3-benzotiazolin-acetamid (smeltepunkt 131 til 132°C) N-/ 2-(N,N-diethylamino)ethyl/-5-trifluoromethyl-2-oxo-3-benzothiazoline-acetamide (m.p. 131 to 132°C)

N-(2-acetbksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-acetboxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 144°C) (melting point 144°C)

Eksempel 2 Example 2

(A) En blanding av etyl-2-okso-3-benzotiazolinacetat (1,2 g), 2-(N,N-dietylamino)etylamin (1.0 g) og vannfri etanol (1.0 g) (A) A mixture of ethyl 2-oxo-3-benzothiazoline acetate (1.2 g), 2-(N,N-diethylamino)ethylamine (1.0 g) and anhydrous ethanol (1.0 g)

oppvarmes under tilbakeløp i 48 timer. Etter fjernelse av etanol ved avdestillering ekstraheres resten med fortynnet saltsyre. Ekstrakten gjøres alkalisk med 10% natriumhydroksydoppløsning og rystes med kloroform. Kloroformskiktet vaskes med vann, tørres og konsentreres. Resten krystalliseres fra etanol og gir N-/2-(N,N-dietylamino)etyl7-2-okso-3-benzotiazo'linacetamid (2.0 g) som fargeløse flak. Smeltepunkt 138,5 til 139,5°C. Basen behandles med maleinsyre på vanlig måte for å danne maleatet. Dette har smeltepunkt 125 til 128°C. heated under reflux for 48 hours. After removal of ethanol by distillation, the residue is extracted with dilute hydrochloric acid. The extract is made alkaline with 10% sodium hydroxide solution and shaken with chloroform. The chloroform layer is washed with water, dried and concentrated. The residue is crystallized from ethanol to give N-(2-(N,N-diethylamino)ethyl7-2-oxo-3-benzothiazolinacetamide (2.0 g) as colorless flakes. Melting point 138.5 to 139.5°C. The base is treated with maleic acid in the usual way to form the maleate. This has a melting point of 125 to 128°C.

(B) En oppløsning av etyl-2-okso-3-benzotiazolinacetat (600 mg) (B) A solution of ethyl 2-oxo-3-benzothiazoline acetate (600 mg)

i overskudd i forhold til l-(2-hydroksyetyl)piperazin oppvarmes ved in excess in relation to l-(2-hydroxyethyl)piperazine is heated by

100°C i omtrent 20 timer. Etter avkjøling tilsettes en stor mengde vann og den resulterende blanding ekstraheres med kloroform. Kloroformekstrakten veskes med vann og rystes med 10% saltsyre. Saltsyreskiktet vaskes med eter, gjøres alkalisk med 20% natrium-hydroksydoppløsning og ekstraheres med kloroform. Kloroformekstrakten vaskes med vann, tørres og konsentreres. Resten krystalliseres fra etanol og gir 3-/4-(2-hydroksyetyl)-l-piperazinylkarbonylmetyl/-2(3H)-benzotiazolinon som krystaller. Maleatet har smeltepunkt 197 til 198°C. (C) En oppløsning av etyl-5-klor-2-okso-3-benzotiazolinacetat (4.0 g) i l-(2-hydroksyetyl)piperazin oppvarmes ved 100°C i 24 timer. 100°C for about 20 hours. After cooling, a large amount of water is added and the resulting mixture is extracted with chloroform. The chloroform extract is diluted with water and shaken with 10% hydrochloric acid. The hydrochloric acid layer is washed with ether, made alkaline with 20% sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried and concentrated. The residue is crystallized from ethanol to give 3-(4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl)-2(3H)-benzothiazolinone as crystals. The maleate has a melting point of 197 to 198°C. (C) A solution of ethyl 5-chloro-2-oxo-3-benzothiazoline acetate (4.0 g) in 1-(2-hydroxyethyl)piperazine is heated at 100°C for 24 hours.

Etter avkjøling ekstraheres den resulterende blanding med kloroform. Kloroformekstrakten vaskes med vann og rystes med 10% saltsyre. Saltsyreskiktet vaskes med kloroform, gjøres alkalisk med 10% natriumhydroksydløsning og ekstraheres med kloroform. Kloroformekstrakten vaskes med vann, tørres over magnesiumsulfat og konsentreres. Den resterende olje (5.5 g) hensettes for å danne krystaller, som omkrystalliseres fra en blanding av etylacetat (40 ml) og etanol (15 ml) og gir 3-/4-(2-hydroksyetyl)-l-piperazinylkarbonyl-metyl/-5-klor-2(3H)-benzotiazolinon (3.2 g) som fargeløse krystaller. Smeltepunkt 159 til 161°C. After cooling, the resulting mixture is extracted with chloroform. The chloroform extract is washed with water and shaken with 10% hydrochloric acid. The hydrochloric acid layer is washed with chloroform, made alkaline with 10% sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate and concentrated. The remaining oil (5.5 g) is set aside to form crystals, which are recrystallized from a mixture of ethyl acetate (40 mL) and ethanol (15 mL) to give 3-(4-(2-hydroxyethyl)-1-piperazinylcarbonyl-methyl) 5-Chloro-2(3H)-benzothiazolinone (3.2 g) as colorless crystals. Melting point 159 to 161°C.

Andre eksempler på forbindelser som kan fremstilles på tilsvarende 'måte omfatter: N-/ 2-(N, N-dietyl amino)-ety 1/-5-klor-2-okso-3-benzotiazolinacetamid Other examples of compounds which can be prepared in a similar manner include: N-[2-(N,N-diethyl amino)-ethyl]-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 127 til 128°C; maleatet har smeltepunkt 119 til 121°C) (melting point 127 to 128°C; the maleate has melting point 119 to 121°C)

N-/3- (N, N-dimetyl amino) propyl_7-2-okso-3-benzotiazol inacetamid N-(3-(N,N-dimethylamino)propyl_7-2-oxo-3-benzothiazole inacetamide

(maleatet har smeltepunkt 155 til 156°C) (the maleate has a melting point of 155 to 156°C)

3-(4-metyl-1-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolin 3-(4-methyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazoline

(smeltepunkt 178 til 179°C) (melting point 178 to 179°C)

N-/2-(N,N-dietylamino) etyl_7-6-metyl-2-okso-3-benzotiazol inacetamid N-(2-(N,N-diethylamino)ethyl_7-6-methyl-2-oxo-3-benzothiazole inacetamide

(maleatet har smeltepunkt 113 til 114.5°C) (the maleate has a melting point of 113 to 114.5°C)

N-^2-(N,N-dietylamino)ety]/7-6-etoksy-2-okso-3-benzotiazolinacetamid. N-^2-(N,N-diethylamino)ethyl]/7-6-ethoxy-2-oxo-3-benzothiazolineacetamide.

(smeltepunkt 131°C) (melting point 131°C)

3-(4-metyl-l-piperazinylkarbonylmetyl)-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 193 til 195°C) 3-(4-Methyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 193 to 195°C)

3-^4-(2-hydroksyetyl)-l-piperazinylkarbonylmetyl/-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 166 til 167.5°C) 3-^4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl/-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 166 to 167.5°C)

3-/4-( 2-hydrok sye ty 1)-1-piper azi nyl karbonyl me tyl_7"-4-kl or-2 (3H)-benzotiazolinon (smeltepunkt 189 til 191°C) 3-(4-(2-Hydroxy 1)-1-piperazi nyl carbonyl methyl-7"-4-chloro-2(3H)-benzothiazolinone (m.p. 189 to 191°C)

3-/ 4-(2-hydroksyety1)-1-piperazinylkarbonylmetyl/-6-klor-2(3H)-benzotiazolinon (smeltepunkt 171 til 173°C) 3-/ 4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl/-6-chloro-2(3H)-benzothiazolinone (m.p. 171 to 173°C)

1-/4-(2-hydroksyety1)-1-piperazinylkarbonyImetyl/-3-metyl-5-klor-2(3H)-benzimidazolinon (smeltepunkt 171 til 173°C) 1-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl)-3-methyl-5-chloro-2(3H)-benzimidazolinone (m.p. 171 to 173°C)

3-(4-hydroksypiperidinokarbonylmetyl)-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 197 til 199°C) 3-(4-hydroxypiperidinocarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 197 to 199°C)

3-/4-(2-hydroksyetyl-l-piperazinylkarbonylmety<l7'-4-klor-2( 3H) - benzotiazolinon (smeltepunkt 189 til 191°C) 3-(4-(2-Hydroxyethyl-1-piperazinylcarbonylmethyl)-4-chloro-2(3H)-benzothiazolinone (m.p. 189 to 191°C)

4'-hydroksy-5-klor-2-okso-3-benzotiazolinacetanilid 4'-Hydroxy-5-chloro-2-oxo-3-benzothiazolineacetanilide

(smeltepunkt 249 til 251°C) (melting point 249 to 251°C)

N-(2-hydroksyetyl)-6-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxyethyl)-6-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 222 til 223°C) (melting point 222 to 223°C)

3-(1-piperazinyl)karbonyl-metyl-5-klor-2(3H)-benzotiazolinon 3-(1-piperazinyl)carbonyl-methyl-5-chloro-2(3H)-benzothiazolinone

(smeltepunkt 211 til 212°C) (melting point 211 to 212°C)

3-/4-(2-hydr ok sypropy 1)-1-piper azi ny lkarbony Ime tyl/-5-kl or-2 (3H) - benzotiazolinon (smeltepunkt 112 til 115°C) 3-/4-(2-Hydroxypropyl)-1-piperazinylcarbonylimethyl/-5-chloro-2(3H)-benzothiazolinone (m.p. 112 to 115°C)

3-(4-acetylmetyl-1-piperazinylkarbonyl-mety1)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 158 til 160°C) 3-(4-Acetylmethyl-1-piperazinylcarbonyl-methyl)-5-chloro-2(3H)-benzothiazolinone (melting point 158 to 160°C)

3-/_4-( 3-hydroksypropyl) -l-piperazinylkarbonylmetyl/-5-klor-2 (3H) - benzotiazolinon (smeltepunkt 118 til 120°C) 3-/_4-(3-hydroxypropyl)-1-piperazinylcarbonylmethyl/-5-chloro-2(3H)-benzothiazolinone (melting point 118 to 120°C)

3-(2,4,5-trimety1-1-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 167 til 173°C) 3-(2,4,5-trimethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 167 to 173°C)

3-/4-(2-hydroksyetyl)-1-piperazinyl-karbonylmetyl/-7-klor-2(3H)-benzotiazolinon (smeltepunkt 170 til 172°C) 3-(4-(2-Hydroxyethyl)-1-piperazinyl-carbonylmethyl)-7-chloro-2(3H)-benzothiazolinone (melting point 170 to 172°C)

3-/_ /4-( 2-hydroksyetyl )-l-piperazinylkarbonylmetyl/-l-ety-l7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 89 til 92°C) 3-/_ /4-( 2-Hydroxyethyl )-1-piperazinylcarbonylmethyl/-1-ethyl-17-5-chloro-2(3H)-benzothiazolinone (m.p. 89 to 92°C)

N-(2-hydroksypropyl)-6-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-6-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 169 til 173°C) (melting point 169 to 173°C)

3-/4-( 2-hydroksyetyl)-1-piper azi nylk arbonyl mety l_7"-6-e tok sy-2 ( 3H)-benzotiazolinon (smeltepunkt 154 til 155°C) 3-/4-(2-Hydroxyethyl)-1-piperazinylk carbonyl methyl 1_7"-6-ethoxy-2(3H)-benzothiazolinone (m.p. 154 to 155°C)

N-/2-(N,N-dicykloheksylamino)etyl/-5-klor-2-okso-3-benzotiazolin-acetamid (smeltepunkt 209 til 210°C) N-(2-(N,N-dicyclohexylamino)ethyl)-5-chloro-2-oxo-3-benzothiazoline-acetamide (m.p. 209 to 210°C)

3-/4- (2-hydroksybutyl) -l-piperazinylkarbonylmety_]^/-5-klor-2-okso-3-benzotiazolinon (smeltepunkt 95 til 98°C) 3-(4-(2-Hydroxybutyl)-1-piperazinylcarbonylmethyl)-5-chloro-2-oxo-3-benzothiazolinone (m.p. 95 to 98°C)

3-/4-(2-etoksykarbonyletyl)-1-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (maleatet har smeltepunkt 152 til 154°C) 3-/4-(2-ethoxycarbonylethyl)-1-piperazinylcarbonylmethyl/-5-chloro-2(3H)-benzothiazolinone (the maleate has a melting point of 152 to 154°C)

3-/2,5-dimetyl-4-(2-hydroksyetyl)-l-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 139 til 141°C) 3-(2,5-dimethyl-4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 139 to 141°C)

3-(2,5-dimety1-4-etoksykarbonylmetyl-1-piperazinylkarbonyImetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 131 til 138°C) 3-(2,5-dimethyl-4-ethoxycarbonylmethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 131 to 138°C)

3-/4-(2-acetoksyetyl)-1-piperazinylkarbonylmetyl7-5-klor-2(3H)-benzotiazolinon (maleatet har smeltepunkt 199.5 til 200°C) 3-(4-(2-acetoxyethyl)-1-piperazinylcarbonylmethyl7-5-chloro-2(3H)-benzothiazolinone (the maleate has a melting point of 199.5 to 200°C)

3-/4-(2-isobutyryloksypropyl)-l-piperazinylkarbonylmetyl7"-5-klor-2(3H)-benzotiazolinon (smeltepunkt 123 til 125°C) 3-(4-(2-isobutyryloxypropyl)-1-piperazinylcarbonylmethyl 7"-5-chloro-2(3H)-benzothiazolinone (m.p. 123 to 125°C)

3-(4-acetylmetyl-1-piperazinylkarbonylmetyl)-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 170 til 172°C) 3-(4-acetylmethyl-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (melting point 170 to 172°C)

3-/4-(2-isobutyrylok syetyl)-1-piper azinylkarbonylmetyl_7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 111 til 113°C) 3-(4-(2-isobutyryloxyethyl)-1-piper azinylcarbonylmethyl_7-5-chloro-2(3H)-benzothiazolinone (m.p. 111 to 113°C)

3-/4-(2-hydroksypropy1)-1-piperazinylkarbonylmety17-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 152.5 til 154°C) 3-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 152.5 to 154°C)

3-^4-(2-acetoksypropyl)-1-piperazinylkarbonylmetyl7-5-klor-2(3H)-benzotiazolinon (hydrokloridet har smeltepunkt 248.til 249°C) 3-^4-(2-acetoxypropyl)-1-piperazinylcarbonylmethyl7-5-chloro-2(3H)-benzothiazolinone (the hydrochloride has a melting point of 248. to 249°C)

N-(2-hydroksypropyl)-5-trifluormetyl-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-5-trifluoromethyl-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 154 til 155°C) (melting point 154 to 155°C)

N-(2-hydroksypropy1)-6-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-6-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 169 til 173°C) (melting point 169 to 173°C)

3-(2,5-dimety1-1-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 285 til 288°C) 3-(2,5-dimethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 285 to 288°C)

3-/4-(l-etoksykarbonyletyl)-1-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 152 til 154°C) 3-(4-(1-ethoxycarbonylethyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 152 to 154°C)

3-(1-piperazinylkarbonyImetyl)-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 163 til 165 C) 3-(1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 163 to 165 C)

3-/4-(1-metyl-2-hydroksyety1)-1-piperazinylkarbonyImetyl7-5-klor-2(3H)<-benzotiazolinon (smeltepunkt 102 til 105°C) 3-(4-(1-methyl-2-hydroxyethyl)-1-piperazinylcarbonylmethyl-7-5-chloro-2(3H)<-benzothiazolinone (m.p. 102 to 105°C)

3-(4-metyl-1-piperaziny1karbonylmety1)-2(3H)-benzotiazolinon 3-(4-methyl-1-piperazinylcarbonylmethyl)-2(3H)-benzothiazolinone

(smeltepunkt 155 til 156°C) (melting point 155 to 156°C)

N-/2-(N,N-dietylamino)ety1/-5-trifluormetyl-2-okso-3-benzotiazolin-acetamid (smeltepunkt 131 til 132°C) N-[2-(N,N-diethylamino)ethyl]-5-trifluoromethyl-2-oxo-3-benzothiazoline-acetamide (m.p. 131 to 132°C)

N-(2-acetoksyety1)-5-klor-2-okso-3-benzotiazolinacetamid (smeltepunkt 144°C), etc. N-(2-acetoxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (melting point 144°C), etc.

Eksempel 3 Example 3

(A) En blanding av 6-klor-2-okso-3-benzotiazolin-eddiksyre (5.04 g) og tionylklorid (50 ml) oppvarmes under tilbakeløp i 2 timer og (A) A mixture of 6-chloro-2-oxo-3-benzothiazoline-acetic acid (5.04 g) and thionyl chloride (50 ml) is heated under reflux for 2 hours and

tionylkloridet avdestilleres. Det således oppnådde 6-klor-2-okso-3-benzotiazolinacetylklorid oppløses i en blanding av benzen (60 ml) og kloroform (30 ml), og den resulterende løsning tilsettes dråpevis til en blanding av benzen (12 ml), 2-aminoetanol (3.4 g), vann (5.6 ml) og natriumkarbonat (1.4 g)' avkjølt med isblandet vann under omrøring. Den resulterende blanding omrøres ved romtemperatur i 40 minutter og etter tilsetning av vann (70 ml) omrøres ennå i noen minutter. Bunnfallet isoleres ved hjelp av filtrering, the thionyl chloride is distilled off. The 6-chloro-2-oxo-3-benzothiazoline acetyl chloride thus obtained is dissolved in a mixture of benzene (60 ml) and chloroform (30 ml), and the resulting solution is added dropwise to a mixture of benzene (12 ml), 2-aminoethanol (3.4 g), water (5.6 ml) and sodium carbonate (1.4 g)' cooled with ice-water with stirring. The resulting mixture is stirred at room temperature for 40 minutes and after the addition of water (70 ml) is further stirred for a few minutes. The precipitate is isolated by means of filtration,

vaskes med vann og omkrystal1 iseres fra en blanding av etanol og kloroform og gir N-(2-hydroksyetyl)-6-klor-2-okso-3-benzotiazolin-acetamid (2.0 g) som hvite bomullslignende krystaller. washed with water and recrystallized from a mixture of ethanol and chloroform to give N-(2-hydroxyethyl)-6-chloro-2-oxo-3-benzothiazoline-acetamide (2.0 g) as white cotton-like crystals.

Smeltepunkt 222 til 223°C. Melting point 222 to 223°C.

(B) En blanding av 5-klor-2-okso-3-benzotiazolin-eddiksyre (4.4 g) og tionylklorid oppvarmes under tilbakeløp i flere timer og tionyl-tkloridet avdestilleres. Det oppnådde 5-klor-2-okso-3-benzotiazolinyl-acetylklorid oppløses i benzen og den resulterende løsning tilsettes dråpevis til en blanding av 2-(2-aminoetoksy)etanol (4.0 g) , natriumkarbonat (2,2 g), vann (12 ml) og benzen (40 ml) avkjølt i et isblandet vannbad under omrøring. Den resulterende blanding omrøres ved romtemperatur i 3 timer og ved 60°C i 30 minutter. (B) A mixture of 5-chloro-2-oxo-3-benzothiazoline-acetic acid (4.4 g) and thionyl chloride is heated under reflux for several hours and the thionyl chloride is distilled off. The 5-chloro-2-oxo-3-benzothiazolinyl acetyl chloride obtained is dissolved in benzene and the resulting solution is added dropwise to a mixture of 2-(2-aminoethoxy)ethanol (4.0 g), sodium carbonate (2.2 g), water (12 mL) and benzene (40 mL) cooled in an ice-water bath with stirring. The resulting mixture is stirred at room temperature for 3 hours and at 60°C for 30 minutes.

Etter avkjøling samles de utskilte krystaller ved filtrering og omkrystalliseres fra vann og gir N-/2-(2-hydroksyetoksy)etyl_7-5-klor-2-okso-3-benzotiazolinacetamid (3,6 g) som fargeløse flak. Smeltepunkt 133 til 134°C. After cooling, the separated crystals are collected by filtration and recrystallized from water to give N-(2-(2-hydroxyethoxy)ethyl_7-5-chloro-2-oxo-3-benzothiazolineacetamide (3.6 g) as colorless flakes. Melting point 133 to 134°C.

Andre eksempler på forbindelser som kan fremstilles på tilsvarende måte omfatter: N-mety1-5-trifluormetyl-2-okso-3-benzotiazolinacetamid Other examples of compounds that can be prepared in a similar manner include: N-methyl-5-trifluoromethyl-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 223 til 224°C) (melting point 223 to 224°C)

N,N-dietyl-5-klor-2-okso-3-benzotiazolinacetamid N,N-diethyl-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 148 til 149°C) (melting point 148 to 149°C)

N-(2-hydroksypropyl)-7-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-7-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 189 til 191°C) (melting point 189 to 191°C)

N-(2-hydroksypropyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 155 til 156°C) (melting point 155 to 156°C)

N-(2-hydroksyety1)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 223 til 224°C) (melting point 223 to 224°C)

N-(2-hydroksyetyl)-N-metyl-5-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxyethyl)-N-methyl-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 115 til 117°C) (melting point 115 to 117°C)

3-(1-piperazinyl)karbonylmetyl-5-klor-2(3H)-benzotiazolinon 3-(1-piperazinyl)carbonylmethyl-5-chloro-2(3H)-benzothiazolinone

(smeltepunkt 211 til 212°C) (melting point 211 to 212°C)

3-/4-( 2-hydr ok sye ty 1)-1-piper azi ny lkarbony lmetyl7"-6-kl or-2 (3H)-benzotiazolinon (smeltepunkt 174 til 176°C) 3-/4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl7"-6-chloro-2(3H)-benzothiazolinone (m.p. 174 to 176°C)

3-/4-(2-hydroksyety1)-1-piperazinylkarbony1mety l/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 159 til 161°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 159 to 161°C)

3-(4-hydroksypiperidinokarbonylmetyl)-5-klor-2(3H)-benzotiazolinon 3-(4-hydroxypiperidinocarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone

(smeltepunkt 178 til 181°C) (melting point 178 to 181°C)

N-/2-(N,N-dietylamino)etyl/-2-okso-3-benzotiazolinacetamid N-(2-(N,N-diethylamino)ethyl)-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 138.5 til 139.5°C) (melting point 138.5 to 139.5°C)

3-/4"-(2-hydrok sye ty 1)-1-piper azi nyl karbonyl me tyl7-2 ( 3H)-benzotiazolinon (maleatet har smeltepunkt 197 til 198°C) 3-/4"-(2-hydroxy sye ty 1)-1-piper azinyl carbonyl methyl 7-2 (3H)-benzothiazolinone (the maleate has a melting point of 197 to 198°C)

3-(4-metyl-1-piperazinylkarbonyImetyl)-5-klor-2(3H)-benzotiazolinon 3-(4-methyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone

(smeltepunkt 178 til 179°C) (melting point 178 to 179°C)

N-(2-etoksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-ethoxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 171 til 173°C) (melting point 171 to 173°C)

3-/4-(2-h<y>dr ok sy<p>rop<y>l)-1-piper azin<y>lkarbon<y>lmet<y>l<7->5-klor-2(3H)-benzotiazolinon (smeltepunkt 104 til 105°C) 3-/4-(2-h<y>dr ok sy<p>rop<y>l)-1-piper azine<y>lcarbon<y>lmet<y>l<7->5-chloro-2 (3H)-Benzothiazolinone (melting point 104 to 105°C)

1 -/4-( 2-hydr ok sye ty 1)-1-piper azi nyl kar bo nyl me tyl_7-3-metyl-5-klor-2(3H)-benzoimidazolinon (smeltepunkt 171 til 173°C) 1-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl-7-3-methyl-5-chloro-2(3H)-benzoimidazolinone (m.p. 171 to 173°C)

1-/ 4-{2-hydroksyetyl)-1-piperazinylkarbonylmety l/-3-mety1-6-klor-2(3H)-benzoimidazolinon (smeltepunkt 172 til 174°C) 1-(4-{2-Hydroxyethyl)-1-piperazinylcarbonylmethyl]-3-methyl-6-chloro-2(3H)-benzoimidazolinone (m.p. 172 to 174°C)

3-/4-(2-hydroksypropyl) -1-pipar azinylkarbonylmetyl7"-3-metyl-6-klor-2(3H)-benzoimidazolinon (smeltepunkt 202 til 206°C) 3-(4-(2-hydroxypropyl)-1-piper azinylcarbonylmethyl 7"-3-methyl-6-chloro-2(3H)-benzoimidazolinone (m.p. 202 to 206°C)

3-(4-acetylmetyl-1-piperazinylkarbonylmety1)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 158 til 160°C) 3-(4-acetylmethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (melting point 158 to 160°C)

3-/^4-(3-hydr ok sypropyl)-1-piper azi nyl karbonyl me tyl^-S-kl or-2 ( 3H) - benzotiazolinon (smeltepunkt 118 til 120°C) 3-[4-(3-hydroxypropyl)-1-piperazinyl carbonyl methyl^-S-chloro-2(3H)-benzothiazolinone (m.p. 118 to 120°C)

3-(2,4,5-trimety1-1-piperazinylkarbonylmety1)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 167 til 173°C) 3-(2,4,5-trimethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 167 to 173°C)

3-/_"4-(2-hydroksyetyl )-l-piperazinylkarbonylmetyl7-7-klor-2( 3H) - benzotiazolinon (smeltepunkt 170 til 172°C) 3-/_"4-(2-Hydroxyethyl )-1-piperazinylcarbonylmethyl7-7-chloro-2( 3H )-benzothiazolinone (melting point 170 to 172°C)

3-/~~/4-( 2-hydroksyetyl)-1-piperazinylkarbonyImetylT-l-etyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 89 til 92°C) 3-[~/4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl-T-1-ethyl]-5-chloro-2(3H)-benzothiazolinone (m.p. 89 to 92°C)

N-(2-hydroksypropyl)-6-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-6-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 169 til 173°C) (melting point 169 to 173°C)

3-/4-(2-hydroksyetyl)-1-piper azi ny lkarbony Ime tyl_7-6-e tok sy-2 (3H) - benzotiazolinon (smeltepunkt 154 til 155°C) 3-(4-(2-Hydroxyethyl)-1-piperaziny lcarbonyl Ime tyl_7-6-e toc sy-2 (3H) - benzothiazolinone (m.p. 154 to 155°C)

Eksempel 4 Example 4

(A) En blanding av 5-klor-2-okso-3-benzotiazolineddiksyre (5.0 g) og tionylklorid (50 ml) oppvarmes under tilbakeløp i 2 timer og (A) A mixture of 5-chloro-2-oxo-3-benzothiazolineacetic acid (5.0 g) and thionyl chloride (50 ml) is heated under reflux for 2 hours and

tionylkloridet avdestilleres. Det således oppnådde 5-klor-2-okso-3-benzotiazolinacetylklorid løses i vannfri benzen (50 ml) og den resulterende løsning tilsettes dråpevis til en blanding av vannfri benzen (100 ml), aziridin (2,3 g), kaliumkarbonat (5.03 g) og vann (15 ml) avkjølt til 5 til 10°C under omrøring. Den resulterende blanding omrøres ved den samme temperatur i 10 minutter. Reaksjonsblandingen vaskes med 10% natriumkarbonatløsning og vann the thionyl chloride is distilled off. The 5-chloro-2-oxo-3-benzothiazoline acetyl chloride thus obtained is dissolved in anhydrous benzene (50 ml) and the resulting solution is added dropwise to a mixture of anhydrous benzene (100 ml), aziridine (2.3 g), potassium carbonate (5.03 g) and water (15 ml) cooled to 5 to 10°C with stirring. The resulting mixture is stirred at the same temperature for 10 minutes. The reaction mixture is washed with 10% sodium carbonate solution and water

i den nevnte rekkefølge og tørres over magnesiumsulfat. Etter fjernelse av løsningsmidler krystalliseres resten fra vannfri benzen og gir 5-klor-3-(l-aziridinyl-karbonylmetyl)-2(3H)-benzotiazolinon (5.0 g) som hvite granuler. Smeltepunkt 137 til 139°C. in the mentioned order and dried over magnesium sulphate. After removal of solvents, the residue is crystallized from anhydrous benzene to give 5-chloro-3-(1-aziridinyl-carbonylmethyl)-2(3H)-benzothiazolinone (5.0 g) as white granules. Melting point 137 to 139°C.

(B) 5.-kl or-3-(l-azir idi ny 1) kar bony Ime ty 1-2 ( 3H) -benzotiazolinon (5.2 g) som fremstilt ovenfor tilsettes til 99% etanol (60 ml) (B) 5.-kl or-3-(l-azir idi ny 1) kar bony Ime ty 1-2 ( 3H)-benzothiazolinone (5.2 g) as prepared above is added to 99% ethanol (60 ml)

og den resulterende blanding oppvarmes under tilbakeløp i 10 minutter. Reaksjonsblandingen settes bort for avkjøling. De utskilte krystaller isoleres ved filtrering og gir N-(2-etoksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid (3,2 g) som hvite flak. Smeltepunkt 171 til 173°C. and the resulting mixture is heated under reflux for 10 minutes. The reaction mixture is set aside to cool. The separated crystals are isolated by filtration and give N-(2-ethoxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (3.2 g) as white flakes. Melting point 171 to 173°C.

På tilsvarende måte kan følgende forbindelser fremstilles: N-/2~-(N, N-dietyl ami no) ety_l_7-2-okso-3-benzotiazol inacetamid In a similar way, the following compounds can be prepared: N-(2~-(N,N-diethylamino)ethyl_1_7-2-oxo-3-benzothiazole inacetamide

(maleatet har smeltepunkt 138.5 til 139.5°C) (the maleate has a melting point of 138.5 to 139.5°C)

N-/2-(N,N-dietylamino)etyl/-5-klor-2-okso-3-benzotiazolinacetamid (smeltepunkt 127 til 128°C). (Maleatet har smeltepunkt 119 til 121°C) N-(2-(N,N-diethylamino)ethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (m.p. 127 to 128°C). (The maleate has a melting point of 119 to 121°C)

N-/2-(N,N-dietylamino)etyl7-6-metyl-2-okso-3-benzotiazolinacetamid N-(2-(N,N-diethylamino)ethyl7-6-methyl-2-oxo-3-benzothiazolineacetamide

(maleatet har smeltepunkt 113 til 114°C) (the maleate has a melting point of 113 to 114°C)

N-/2*-(N, N-dietyl ami no) etyl/-6-etoksy-2-okso-3-benzotiazol inacetamid N-[2*-(N,N-diethyl amino)ethyl]-6-ethoxy-2-oxo-3-benzothiazole inacetamide

(smeltepunkt 131°C) (melting point 131°C)

N-/2-(N, N-dietyl amino) etyl_/-3-metyl-6-klor-2-okso-l-benzimidazol inacetamid (smeltepunkt 124 til 125°C) N-/2-(N,N-diethyl amino)ethyl_/-3-methyl-6-chloro-2-oxo-1-benzimidazole inacetamide (melting point 124 to 125°C)

N-/2-(N, N-dietyl amino )ety_l7"_5-tr if luormetyl-2-okso-3-benzoti azol inacetamid (smeltepunkt 131 til 132°C). N-(2-(N,N-diethylamino)ethyl_17"_5-trifluoromethyl-2-oxo-3-benzothiazole inacetamide (m.p. 131 to 132°C).

(C) En blanding av 5-klor-2-okso-3-benzotiazolineddiksyre (2.0 g) og tionylklorid (20 ml) oppvarmes under tilbakeløp i 2 timer og (C) A mixture of 5-chloro-2-oxo-3-benzothiazolineacetic acid (2.0 g) and thionyl chloride (20 mL) is heated under reflux for 2 hours and

tionylklorid avdestilleres. Det således oppnådde 5r-klor-2-okso-3-benzotiazolinacetylklorid oppløses i vannfri benzen (20 ml), thionyl chloride is distilled off. The thus obtained 5r-chloro-2-oxo-3-benzothiazoline acetyl chloride is dissolved in anhydrous benzene (20 ml),

og den resulterende løsning tilsettes dråpevis. til en blanding av aziridin (0.424 g) og vannfri benzen (10 ml) holdt ved 10 til 15°C under omrøring. Den resulterende blanding omrøres ved romtemperatur i 3 timer og settes bort over natten. Etter fjernelse av løsningsmidlet oppløses resten i en blanding av vann (50 ml) og 10% natriumhydrogenkarbonatløsning (80 ml) og den resulterende oppløsning omrøres i flere minutter. De utskilte krystaller isoleres ved filtrering, vaskes med vann, oppløses i en blanding av etanol (70 ml) og aceton (30 ml) og behandles med aktivkull. Deretter konsentreres oppløsningen til omtrent 60 ml og settes bort over natten. De utskilte krystaller samles ved filtrering og omkrystalliseres fra etanol og gir N-(2-kloretyl)-5-klor-2-okso-3-benzotiazolinacetamid (1,2 g) som hvite krystaller. and the resulting solution is added dropwise. to a mixture of aziridine (0.424 g) and anhydrous benzene (10 ml) kept at 10 to 15°C with stirring. The resulting mixture is stirred at room temperature for 3 hours and set aside overnight. After removal of the solvent, the residue is dissolved in a mixture of water (50 ml) and 10% sodium bicarbonate solution (80 ml) and the resulting solution is stirred for several minutes. The separated crystals are isolated by filtration, washed with water, dissolved in a mixture of ethanol (70 ml) and acetone (30 ml) and treated with activated charcoal. The solution is then concentrated to approximately 60 ml and set aside overnight. The precipitated crystals are collected by filtration and recrystallized from ethanol to give N-(2-chloroethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide (1.2 g) as white crystals.

Smeltepunkt 192 til 194°C. Melting point 192 to 194°C.

(T>) 2-okso-3-benzotiazolineddiksyre behandles som ovenfor og (T>) 2-oxo-3-benzothiazolineacetic acid is treated as above and

«gir N-(2-kloretyl)-2-okso-3-benzotiazolinacetamid. Smeltepunkt «gives N-(2-chloroethyl)-2-oxo-3-benzothiazolineacetamide. Melting point

159 til 162°C. 159 to 162°C.

Eksempel 5 Example 5

N-(2-kloretyl)-2-okso-3-benzotiazolinacetamid (1.0 g) og dietylamin (1.62 g) innføres i et trykkrør av stål og oppvarmes ved 90°C i 5-J time. Deretter/tilsettes 10% saltsyre og etylacetat. Etylacetatskiktet"ekstraheres méd 10% saltsyre. Saltsyreekstrakten og saltsyreskiktet kombineres, vaskes med etylacetat, gjøres alkalisk med 10% natriumhydroksydløsning. De isolerte krystaller ekstraheres med kloroform. Klorof ormekstrakten vaskes med vann, tørres over vannfritt magnesiumsulfat og konsentreres. Den oljeaktige rest krystalliseres fra petroleumbensin og omkrystalliseres fra etanol og gir N-/^-(N,N-dietylamino)ety_l7-2-okso-3-benzotiazolin-acetamid (0.45 g) som fargeløse skjell. Smeltepunkt 138.5 til 139.5°C. N-(2-chloroethyl)-2-oxo-3-benzothiazolineacetamide (1.0 g) and diethylamine (1.62 g) are introduced into a steel pressure tube and heated at 90° C. for 5-1 hour. 10% hydrochloric acid and ethyl acetate are then added. The ethyl acetate layer" is extracted with 10% hydrochloric acid. The hydrochloric acid extract and the hydrochloric acid layer are combined, washed with ethyl acetate, made alkaline with 10% sodium hydroxide solution. The isolated crystals are extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate and concentrated. The oily residue is crystallized from petroleum benzine and recrystallized from ethanol to give N-(N,N-diethylamino)ethyl-17-2-oxo-3-benzothiazoline-acetamide (0.45 g) as colorless shells, mp 138.5 to 139.5°C.

Andre eksempler på forbindelser som kan fremstilles på lignende Other examples of compounds that can be prepared in a similar way

måte inkluderer: N-/2-(N,N-dietylamino)etyl/-2-okso-3-benzotiazolinacetamid way includes: N-/2-(N,N-diethylamino)ethyl/-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 138.5 til 139.5°C) (melting point 138.5 to 139.5°C)

N-/2-(N,N-dicykloheksylamino)etyl7-5-klor-2-okso-3-benzotiazolin-acetamid (smeltepunkt 209 til 210°C) N-(2-(N,N-dicyclohexylamino)ethyl 7-5-chloro-2-oxo-3-benzothiazoline-acetamide (m.p. 209 to 210°C)

N-/2-(N, N-dietyl amin) etyl/-5-klor-2-okso-3-benzotiazol inacetamid N-(2-(N,N-diethylamine)ethyl)-5-chloro-2-oxo-3-benzothiazole inacetamide

(smeltepunkt 127 til 128°C. Maleatet har smeltepunkt 119 til 121°C) (melting point 127 to 128°C. The maleate has a melting point 119 to 121°C)

N-/2-(N,N-dietylamino)etyl/7-6-metyl-2-okso-3-benzotiazolinacetamid N-(2-(N,N-diethylamino)ethyl/7-6-methyl-2-oxo-3-benzothiazolineacetamide

(maleatet har smeltepunkt 113 til 114°C) (the maleate has a melting point of 113 to 114°C)

N-/_2-(N, N-dietyl amino) etyl7-6-etoksy-2-okso-3-benzotiazolin-acetamid (smeltepunkt 131°C) N-(N,N-diethylamino)ethyl7-6-ethoxy-2-oxo-3-benzothiazoline-acetamide (melting point 131°C)

N-/2-(N,N-dietylamino)etyl7-3-metyl-6-klor-2-okso-l-benzimidazolin-acetamid (smeltepunkt 124 til 125°C) N-(2-(N,N-diethylamino)ethyl7-3-methyl-6-chloro-2-oxo-1-benzimidazoline-acetamide (m.p. 124 to 125°C)

N-£2-(N,N-dietylamino)etyl7-5-trifluormetyl-2-okso-3-benzotiazolin-acetamid (smeltepunkt 131 til 132°C) N-£2-(N,N-diethylamino)ethyl7-5-trifluoromethyl-2-oxo-3-benzothiazoline-acetamide (m.p. 131 to 132°C)

Eksempel 6 Example 6

Til en løsning av 3-(l-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (0,45 g) i metanol (30 ml), tilsettes propylenoksyd (0,25 g), og den resulterende blanding oppvarmes ved 50°C To a solution of 3-(1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (0.45 g) in methanol (30 mL) is added propylene oxide (0.25 g) and the resulting mixture heated at 50°C

i 5 timer hvorunder det to ganger tilsettes propylenoksyd (0.3 g). Reaksjonsblåndingen konsentreres under redusert trykk. Den resterende olje krystalliseres fra petroleumbensin og omkrystal1iseres fra en blanding av etylacetat og petroleumbensin og gir for 5 hours during which propylene oxide (0.3 g) is added twice. The reaction mixture is concentrated under reduced pressure. The remaining oil is crystallized from petroleum gasoline and recrystallized from a mixture of ethyl acetate and petroleum gasoline and gives

3-/4-( 2-hydroksypropyl)-l-piperazinylkarbonylmetyl7'-5-klor-2(3H) - benzotiazolinon (0.43 g) som fargeløse nåler. Smeltepunkt 112 3-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl7'-5-chloro-2(3H)-benzothiazolinone (0.43 g) as colorless needles. Melting point 112

til 115°C. to 115°C.

Andre eksempler på forbindelser som kan fremstilles på tilsvarende måte ved anvendelse av 4, 5, 6 eller 7-substituert eller usubstituert 3-/1-piperazinylkarbonyl(lavere)alkyl/-2(3H)-benzotiazolinon som utgangsforbindelser omfatter: 3-/4-(2-hydroksybuty1)-1-piperazinylkarbonyImetyl7_5-klor-2(3H)-benzotiazolinon (smeltepunkt 95 til 98°C). Other examples of compounds that can be prepared in a similar manner using 4, 5, 6 or 7-substituted or unsubstituted 3-/1-piperazinylcarbonyl(lower)alkyl/-2(3H)-benzothiazolinone as starting compounds include: 3-/4 -(2-Hydroxybutyl)-1-piperazinylcarbonylmethyl-7-5-chloro-2(3H)-benzothiazolinone (m.p. 95 to 98°C).

Andre eksempler på forbindelser som kan fremstilles på lignende Other examples of compounds that can be prepared in a similar way

måte omfatter: 3-^4-(2-hydroksyetyl)-l-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 159 til 161°C) method includes: 3-[4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl]-5-chloro-2(3H)-benzothiazolinone (m.p. 159 to 161°C)

3-/4-(2-hydroksyetyl)-1-piperazinylkarbonylmety^/-6-klor-2(3H)-benzotiazolinon (smeltepunkt 175 til 177°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl)-6-chloro-2(3H)-benzothiazolinone (m.p. 175 to 177°C)

3-/4-(2-hydroksyetyl)-1-piperazinylkarbonylmetyl7~5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 166 til 167,5°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl-7~5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 166 to 167.5°C)

3-_/4-(2-hydr ok sy etyl)-1-piper azinyl karbonyl mety l_7"-4-kl or-2 ( 3H)-benzotiazolinon (smeltepunkt 189 til 191°C) 3-_/4-(2-Hydroxyethyl)-1-piper azinyl carbonyl methyl 7"-4-chloro-2(3H)-benzothiazolinone (m.p. 189 to 191°C)

N-(2-hydroksypropyl)-7-kloir-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-7-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 189 til 191°C) (melting point 189 to 191°C)

N-(2-hydroksypropyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxypropyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 155 hil 156°C) (melting point 155 hil 156°C)

N-(2-hydroksyetyl)-5-klor-2-okso-3-benzotiazolinacetamid N-(2-hydroxyethyl)-5-chloro-2-oxo-3-benzothiazolineacetamide

(smeltepunkt 223 til 224°C) (melting point 223 to 224°C)

1-/4-(2-hydroksyetyl)-1 -piper aziny lkarbony Ime tyl_7-3-metyl-6-klor-2(3H)-benzimidazolinon (smeltepunkt 172 til 174°C) 1-(4-(2-Hydroxyethyl)-1-piperazinylcarbonyl)-methyl-7-3-methyl-6-chloro-2(3H)-benzimidazolinone (m.p. 172 to 174°C)

1-/4-(2-hydroksypropyl)-1-piperazinylkarbonylmetyl_7-3-metyl-6-klor-2(3H)-benzoimidazolinon (smeltepunkt 202 til 206°C) 1-(4-(2-hydroxypropyl)-1-piperazinylcarbonylmethyl_7-3-methyl-6-chloro-2(3H)-benzoimidazolinone (m.p. 202 to 206°C)

3-/4-(2-hydroksyetyl)-1-piperazinylkarbonylmetyl7-6-etoksy-2(3H)-benzotiazolinon (smeltepunkt 154 til 155.5°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl7-6-ethoxy-2(3H)-benzothiazolinone (melting point 154 to 155.5°C)

3-/2,5-dimety1-4-(2-hydroksyetyl)-1-piperazinylkarbonylmetyl7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 139 til 141°C) 3-(2,5-dimethyl-4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl-7-5-chloro-2(3H)-benzothiazolinone (m.p. 139 to 141°C)

3-/4-(2-hydr ok syetyl)-1-piper azi nylk ar bonylmetyl_7-7-kl or-2 (3H)-benzotiazolinon (smeltepunkt 170 til 172°C) 3-(4-(2-hydroxyethyl)-1-piperazinylkarbonylmethyl_7-7-chloro-2(3H)-benzothiazolinone (melting point 170 to 172°C)

3-/T-/4"-(2-hydroksyetyl)-l-piperazinylkarbony]petyl7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 89 til 92°C) 3-/T-/4"-(2-Hydroxyethyl)-1-piperazinylcarbonyl]petyl7-5-chloro-2(3H)-benzothiazolinone (m.p. 89 to 92°C)

3-/4-(2-hydroksypropyl)-1-piperazinylkarbonylmetyl7-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 152.5 til 154.5°C) 3-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl-7-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 152.5 to 154.5°C)

3-/4"-(2-hydroksyetyl)-1-piper azi nyl karbony Ime tyl7-2 (3H) -benzotiazolinon (maleatet har smeltepunkt 197 til 198°C) 3-/4"-(2-Hydroxyethyl)-1-piperazinyl carbonyl Ime tyl7-2(3H)-benzothiazolinone (the maleate has a melting point of 197 to 198°C)

1-/4-(2-hydroksyety1)-1-piperazinylkarbonyImety l7-3-metyl-5-klor-2(3H)-benzimidazolinon (smeltepunkt 171 til 173°C), etc. 1-(4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl 7-3-methyl-5-chloro-2(3H)-benzimidazolinone (m.p. 171 to 173°C), etc.

Eksempel 7 Example 7

En blanding av 3-(l-piperazinyl)karbpnylmetyl-5-klor-2(3H)-benzotiazolinon (500 mg), vanrifritt kaliumkarbonat (400 mg), 2- hydroksyetylbromid (300 mg) og vannfri etanol (20 ml) ble oppvarmet under tilbakeløp i 5 timer. Reaksjonsblåndingen ble konsentrert under redusert trykk. Resten ekstraheres med kloroform. Kloroformskiktet tørres over magnesiumsulfat og konsentreres. Resten krystalliseres frab en blanding av etylacetat og etanol og gir 3-/4"-( 2-hy dr ok sy ety 1-1-piper azi nyl karbony 1-me tyl7-5-kl or-2 (3H)-benzotiazolinon (370 mg) som krystaller. A mixture of 3-(1-piperazinyl)carbynylmethyl-5-chloro-2(3H)-benzothiazolinone (500 mg), anhydrous potassium carbonate (400 mg), 2-hydroxyethyl bromide (300 mg) and anhydrous ethanol (20 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue is extracted with chloroform. The chloroform layer is dried over magnesium sulfate and concentrated. The residue is crystallized from a mixture of ethyl acetate and ethanol and gives 3-/4"-( 2-hydroxyethyl 1-1-piperazinyl carbonyl 1-methyl7-5-chloro-2(3H)-benzothiazolinone ( 370 mg) as crystals.

Smeltepunkt 159 til 160°C. Melting point 159 to 160°C.

Andre eksempler på forbindelser som kan fremstilles på lignende måte under anvendelse av 4, 5, 6 eller 7-substituert eller usubstituert 3-(1-piperaziny1)karbonyl(lavere)alkyl-2(3H)-benzotiazolinon som utgangsforbindelse inkluderer: 3-/4-(1-etoksykarbonyletyl)-1-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (maleatet har smeltepunkt 152 til 154°C) Other examples of compounds that can be prepared in a similar manner using 4, 5, 6 or 7-substituted or unsubstituted 3-(1-piperazinyl)carbonyl(lower)alkyl-2(3H)-benzothiazolinone as starting compound include: 3-/ 4-(1-ethoxycarbonylethyl)-1-piperazinylcarbonylmethyl/-5-chloro-2(3H)-benzothiazolinone (the maleate has a melting point of 152 to 154°C)

3-(4-acetylmety1-1-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (smeltepunkt 158 til 160°C) 3-(4-acetylmethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (melting point 158 to 160°C)

3-/4-(3-hydroksypropyl)-1-piperazinylkarbonyImetyl7-5-klor-2(3H)-benzotiazolinon (smeltepunkt 118 til 120°C) 3-(4-(3-Hydroxypropyl)-1-piperazinylcarbonylmethyl-7-5-chloro-2(3H)-benzothiazolinone (m.p. 118 to 120°C)

3-/2 ,5-dimetyl-4-(2-hydroksyetyl)-l-piperazinylkarbonylmety]V-5-klor-2(3H)-benzotiazolinon (smeltepunkt 139 til 140°C) 3-(2,5-dimethyl-4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl)N-5-chloro-2(3H)-benzothiazolinone (m.p. 139 to 140°C)

3-/4-(2-hydroksypropyl)-1-piperazinylkarbonyImetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 112 til 115°C) 3-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 112 to 115°C)

3-/4-(2-hydroksybutyl)-1-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 95 til 98°C) 3-(4-(2-Hydroxybutyl)-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (m.p. 95 to 98°C)

3-/4-(2-hydroksyetyl)-1-piperazinylkarbonyImetyl7-6-klor-2(3H)-benzotiazolinon (smeltepunkt 175 til 177°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl-7-6-chloro-2(3H)-benzothiazolinone (melting point 175 to 177°C)

>3-/4-(2-hydroksyetyl)-1-piperazinylkarbonylmetyl7-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 166 til 167.5°C) >3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl7-5-trifluoromethyl-2(3H)-benzothiazolinone (melting point 166 to 167.5°C)

3-/4- (2-hydroksyetyl)-1-piperazinylkarbonylmetyl/-4-klor-2 (3H)-benzotiazolinon (sme ltepunkt 189 til 191 C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl)-4-chloro-2(3H)-benzothiazolinone (m.p. 189 to 191 C)

1-/4-(2-hydroksyetyl)-1-piperazinylkarbonyImetyl7-3-metyl-6-klor-2(3H)-benzimidazolinon (smeltepunkt 172 til 174°C) 1-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl-7-3-methyl-6-chloro-2(3H)-benzimidazolinone (m.p. 172 to 174°C)

1-/4-(2-hydroksypropyl)-1-piperazinylkarbonylmetyl7-3-mety1-6-klor-2(3H)-benzimidazolinon (smeltepunkt 202 til 206°C) 1-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl-7-3-methyl-6-chloro-2(3H)-benzimidazolinone (m.p. 202 to 206°C)

3-/4-C2-hydroksyetyl)-l-piperazinylkarbonylmetyl7-6-etoksy-2(3H)-benzotiazolinon (smeltepunkt 154 til 155.5°C) 3-(4-C2-hydroxyethyl)-1-piperazinylcarbonylmethyl7-6-ethoxy-2(3H)-benzothiazolinone (melting point 154 to 155.5°C)

3-/4-(2-hydroksyetyl)-1-piperazinylkarbonylmetyl7-7-klor-2(3H)-benzotiazolinon (smeltepunkt 170 til 172°C) 3-(4-(2-Hydroxyethyl)-1-piperazinylcarbonylmethyl7-7-chloro-2(3H)-benzothiazolinone (melting point 170 to 172°C)

3//T-/4-( 2-hydroksyetyl)-1-piper azi nylk arbonyj/7etyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 89 til 92°C) 3//T-/4-(2-Hydroxyethyl)-1-piperazinylkarbony/7ethyl/-5-chloro-2(3H)-benzothiazolinone (m.p. 89 to 92°C)

3-/4-(2-hydroksypropyl) -1-piperazinylkarbonylmetyl7-5-trifluormetyl-2(3H)-benzotiazolinon (smeltepunkt 152.5 til 154°C) 3-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl-7-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 152.5 to 154°C)

3-/4- (2-hydr ok sye tyl )-1-piper azi nyl karbony lmetyl_7"-2 ( 3H) -benzotiazolinon (maleatet har smeltepunkt 197 til 198°C) 3-/4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl_7"-2(3H)-benzothiazolinone (the maleate has a melting point of 197 to 198°C)

1-/4-(2-hydroksyetyl)-1-piper azinyl karbony Ime ty l7"-3-me tyl-5-klor-2(3H)-benzimidazolinon (smeltepunkt 171 til 173°C), etc' 1-(4-(2-Hydroxyethyl)-1-piper azinyl carbonyl Ime ty 17"-3-methyl-5-chloro-2(3H)-benzimidazolinone (m.p. 171 to 173°C), etc'

Eksempel 8 Example 8

Til en blanding av 3-/4-(2-hydroksyetyl)-l-piperazinylkarbonyl-metyl7'-5-klor-2( 3H)-benzotiazolinon (1,42 g), kaliumkarbonat (1,4 g) og kloroform (40 ml) tilsettes dråpevis en blanding av acetylklorid (0.8 g) og tetrahydrofuran (5 ml) under avkjøling i løpet av omtrent 30 minutter. Den resulterende blanding omrøres ved romtemperatur i 6 timer. Reaksjonsblandingen vaskes med vann, tørres og konsentreres og gir 3-/4-(2-acetyloksyetyl)-1-piperazinyl-karbonylmetyl7"-5-klor-2(3H)-benzotiazolinon som en fargeløs olje. Oljen behandles med maleinsyre og det resulterende maleat To a mixture of 3-(4-(2-hydroxyethyl)-1-piperazinylcarbonyl-methyl7'-5-chloro-2(3H)-benzothiazolinone (1.42 g), potassium carbonate (1.4 g) and chloroform (40 ml) is added dropwise to a mixture of acetyl chloride (0.8 g) and tetrahydrofuran (5 ml) while cooling over approximately 30 minutes. The resulting mixture is stirred at room temperature for 6 hours. The reaction mixture is washed with water, dried and concentrated to give 3-(4-(2-acetyloxyethyl)-1-piperazinylcarbonylmethyl7"-5-chloro-2(3H)-benzothiazolinone as a colorless oil. The oil is treated with maleic acid and the resulting maleate

krystalliseres fra etanol til fargeløse flak. Smeltepunkt crystallizes from ethanol to colorless flakes. Melting point

199.5 til 200°C. 199.5 to 200°C.

Andre eksempler på forbindelser som kan fremstilles på lignende måte inkluderer: 3_/4,-/2-(i sobutyry lok sy) propyl_7-l-piper azi ny lkarbony Ime tyl_7-5-k lor - 2(3H)-benzotiazolinon (smeltepunkt 123 til 125°C) 3-/4-/2-(isobutyryloksy) etyl/-l-piperazinylkarbonylmetyl/-5-klor-2(3H)-benzotiazolinon (smeltepunkt 111 til 113°C) Other examples of compounds that can be prepared in a similar manner include: 3_/4,-/2-(i sobutyryl loc sy) propyl_7-l-piper azi ny lcarbony Ime tyl_7-5-chlor - 2(3H)-benzothiazolinone (melting point 123 to 125°C) 3-/4-/2-(isobutyryloxy)ethyl/-1-piperazinylcarbonylmethyl/-5-chloro-2(3H)-benzothiazolinone (m.p. 111 to 113°C)

3-/4-/2-( acetyl ok sy) propyjj^-l-piper azi nyl karbony lmetyl_7"-5-klor-2(3H)-benzotiazolinon 3-/4-/2-(acetyl ok sy)propyjj^-1-piperazi nyl carbonyl lmethyl_7"-5-chloro-2(3H)-benzothiazolinone

3-/4-(2-isobutyryloksyetyl)-1-piperazinylkarbonyImetyl7-6-etoksy-2(3H)-benzotiazolinon, etc. 3-(4-(2-isobutyryloxyethyl)-1-piperazinylcarbonylmethyl-7-6-ethoxy-2(3H)-benzothiazolinone, etc.

Eksempel 9 Example 9

Til en løsning av 3-(4-acetylmetyl-l-piperazinylkarbonylmetyl)-5-klor-2(3H)-benzotiazolinon (0.3 g) i metanol (15 ml) tilsettes porsjonsvis natriumborhydrid (0.3 g) ved romtemperatur og den resulterende blanding settes bort i 30 minutter. Etter fjernelse av metanol fra reaksjonsblandingen ved destillasjon blandes resten med vann (20 ml) og det vandige skikt ekstraheres med etylacetat. Ekstrakten tørres og konsentreres. Petroleumbensin tilsettes til resten slik at oljen felles ut. Oljen isoleres ved dekantering, får størkne og krystalliseres fra en blanding av etylacetat og petroleumbensin og gir 3-/4-(2-hydroksypropyl)-1-piperazinyl-karbonylmetyl7-5-klor-2(3H)-benzotiazolinon (0.2 g) som fargeløse krystaller. Smeltepunkt 104 til 105°C. To a solution of 3-(4-acetylmethyl-1-piperazinylcarbonylmethyl)-5-chloro-2(3H)-benzothiazolinone (0.3 g) in methanol (15 ml) is added portionwise sodium borohydride (0.3 g) at room temperature and the resulting mixture is away for 30 minutes. After removal of methanol from the reaction mixture by distillation, the residue is mixed with water (20 ml) and the aqueous layer is extracted with ethyl acetate. The extract is dried and concentrated. Petroleum petrol is added to the residue so that the oil precipitates out. The oil is isolated by decantation, allowed to solidify and crystallized from a mixture of ethyl acetate and petroleum petrol and gives 3-(4-(2-hydroxypropyl)-1-piperazinylcarbonylmethyl7-5-chloro-2(3H)-benzothiazolinone (0.2 g) as colorless crystals. Melting point 104 to 105°C.

Andre eksempler på forbindelser som kan fremstilles på lignende måte inkluderer: 3-/4-(2-hydroksypropyl)-1-piperazinylkarbonylmetyl/-5-trif1uor-metyl-2(3H)-benzotiazolinon (smeltepunkt 152.5 til 154°C) Other examples of compounds which can be prepared in a similar manner include: 3-(4-(2-hydroxypropyl)-1-piperazinylcarbonylmethyl)-5-trifluoromethyl-2(3H)-benzothiazolinone (m.p. 152.5 to 154°C)

1-/4-(2-hydroksypropyl)-1-piperazinylkarbonylmety 17-6-klor-2(3H)-benzimidazolinon (smeltepunkt 202 til 206°C), etc. 1-(4-(2-Hydroxypropyl)-1-piperazinylcarbonylmethyl 17-6-chloro-2(3H)-benzimidazolinone (m.p. 202 to 206°C), etc.

Eksempel 10 Example 10

(A) En blanding av etyl-6-klor-3-metyl-2-okso-l-benzimidazolin-acetat (0.5 g) og 2-(N,N-dietylamino)-etylamin (2,5 g) oppvarmes (A) A mixture of ethyl 6-chloro-3-methyl-2-oxo-1-benzimidazoline acetate (0.5 g) and 2-(N,N-diethylamino)-ethylamine (2.5 g) is heated

ved 110°C i 20 timer. Reaksjonsblandingen oppløses i kloroform at 110°C for 20 hours. The reaction mixture is dissolved in chloroform

(100 ml) og vaskes med vann. Kloroformskiktet ekstraheres med 10% saltsyre. Sal tsyreskiktet vaskes med kloroform, gj øres alkalisk med 10% natriumhydroksydløsning og ekstraheres med kloroform. Kloroformekstrakten vaskes med vann, tørres over vannfritt magnesiumsulfat og konsentreres under redusert trykk. Resten vaskes med petroleumbensin og krystalliseres fra en blanding av benzen og petroleumbensin og gir N-_/2~(N, N-dietyl amino) etyl7-6-klor-3-metyl-2-okso-l-benzimidazolinacetamid (0.2 g) som hvite krystaller. Smeltepunkt 124 til 126°C. (100 ml) and washed with water. The chloroform layer is extracted with 10% hydrochloric acid. The brine layer is washed with chloroform, made alkaline with 10% sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is washed with petroleum benzine and crystallized from a mixture of benzene and petroleum benzine to give N-_/2~(N,N-diethyl amino)ethyl7-6-chloro-3-methyl-2-oxo-1-benzimidazoline acetamide (0.2 g) as white crystals. Melting point 124 to 126°C.

(B) En' blanding av etyl-5-klor-3-metyl-2-okso-l-benzimidazolin-acetat (0.3 g) og l-(2-hydroksyetyl)-piperazin (1.0 ml) oppvarmes (B) A mixture of ethyl 5-chloro-3-methyl-2-oxo-1-benzimidazoline acetate (0.3 g) and 1-(2-hydroxyethyl)-piperazine (1.0 ml) is heated

ved 110°C i 15 timer. Reaksjonsblandingen kombineres med etylacetat, vaskes med vann og ekstraheres med 10% saltsyre. Saltsyreekstrakten vaskes med kloroform og gjøres alkalisk med 10% natriumhydroksydløsning under avkjøling med is. Den alkaliske løsning ekstraheres med kloroform. Kloroformekstrakten tørres over.magnesiumsulfat og konsentreres under redusert trykk. Resten krystalliseres fra petroleumbensin og omkrystalliseres fra etylacetat og gir l-/4-(2-hydroksyetyl)-l-piperazinylkarbonylmetyl_7-5-klor-3-metyl-2-oksobenzimidazolin (0.3 g) som fargeløse nåler. Smeltepunkt 173 til 174°C. at 110°C for 15 hours. The reaction mixture is combined with ethyl acetate, washed with water and extracted with 10% hydrochloric acid. The hydrochloric acid extract is washed with chloroform and made alkaline with 10% sodium hydroxide solution while cooling with ice. The alkaline solution is extracted with chloroform. The chloroform extract is dried over magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from petroleum benzine and recrystallized from ethyl acetate to give 1-(4-(2-hydroxyethyl)-1-piperazinylcarbonylmethyl-7-5-chloro-3-methyl-2-oxobenzimidazoline (0.3 g) as colorless needles. Melting point 173 to 174°C.

Andre eksempler på forbindelser som kan fremstilles på tilsvarende måte inkluderer: 1-/j4-( 2-hy drok sye tyl )-1-piper azi nylk arbonylmetyl7-3-metyl-6-klor-2(3H)-benzimidazolinon (smeltepunkt 172 til 174°C) 1 -/4-(2-hydroksypropyl-1-piperazinylkarbonylmetyl7-3-metyl-6-klor-2(3H)-benzimidazolinon (smeltepunkt 202 til 206°C), etc. Other examples of compounds which can be prepared in a similar manner include: 1-[j4-(2-hydroxyethyl)-1-piperazinylk carbonylmethyl7-3-methyl-6-chloro-2(3H)-benzimidazolinone (m.p. 172 to 174°C) 1 -/4-(2-Hydroxypropyl-1-piperazinylcarbonylmethyl-7-3-methyl-6-chloro-2(3H)-benzimidazolinone (m.p. 202 to 206°C), etc.

Claims (1)

Analogifremgangsmåte for fremstilling av nye, terapeutisk aktive benzotiazol- og benzimidazol-forbindelser med den generelle formel hvori 2 er svovel eller lavere alkylimino,Analogous process for the preparation of new, therapeutically active benzothiazole and benzimidazole compounds of the general formula wherein 2 is sulfur or lower alkylimino, A er alkylen med 1-3 karbonatomer, fortrinnsvis metylen, R er hydrogen, halogen, lavere alkyl, lavere alkoksy ellerA is the alkylene with 1-3 carbon atoms, preferably methylene, R is hydrogen, halogen, lower alkyl, lower alkoxy or trifluormetyl, 2trifluoromethyl, 2 R er hydrogen eller lavere alkyl,R is hydrogen or lower alkyl, R er lavere alkyl, halo(lavere)alkyl, hydroksyClavere)R is lower alkyl, halo(lower)alkyl, hydroxyClavere) alkyl, lavere alkanoyloksy(lavere)alkyl, lavere alkoksy(lavere) alkyl, hydroksy(lavere) alkoksyd avere) alkyl, hydroksyfenyl, eller en gruppe med den generelle formel 4 5 hvori A' er lavere alkylen og R og R er hver lavere alkyl eller cykloalkyl med 3-6 karbonatomer, eller gruppen med formelen:alkyl, lower alkanoyloxy (lower) alkyl, lower alkoxy (lower) alkyl, hydroxy (lower) alkoxide avere) alkyl, hydroxyphenyl, or a group of the general formula 4 5 wherein A' is lower alkylene and R and R are each lower alkyl or cycloalkyl with 3-6 carbon atoms, or the group with the formula: står enten for aziridinyl, piperidino som kan være substituert med hydroksy, eller piperazinyl som kan være substituert med opp til 2 lavere alkylradikaler og nitrogenatomet i 4-stillingen kan i tillegg være substituert med lavere alkyl, hydroksy(lavere)alkyl, lavere alkanoyl(lavere)alkyl, lavere alkanoyloksy(lavere)alkyl eller lavere alkoksykarbonyl (1avere)alkyl, 1 2 3stands either for aziridinyl, piperidino which can be substituted with hydroxy, or piperazinyl which can be substituted with up to 2 lower alkyl radicals and the nitrogen atom in the 4-position can also be substituted with lower alkyl, hydroxy(lower)alkyl, lower alkanoyl(lower )alkyl, lower alkanoyloxy(lower)alkyl or lower alkoxycarbonyl(1avere)alkyl, 1 2 3 idet R" ikke er hydrogen nar R og R hver er lavere alkvl ellerwherein R" is not hydrogen when R and R are each lower alkyl or står for aziridinyl eller piperidino karakterisert ved at enten (a) en forbindelse med den generelle formelstands for aziridinyl or piperidino characterized in that either (a) a compound of the general formula hvori Z og R"<*>" har den ovennevnte betydning, eller et reaktivt derivat derav, omsettes med et alkylhalogenid med den generelle formelin which Z and R"<*>" have the above meaning, or a reactive derivative thereof, is reacted with an alkyl halide of the general formula hvori X er halogen, R 2 og R 3samt A har den ovennevnte betydning, eller (b) en forbindelse med den generelle formel hvori Z, A og R^" har den ovennevnte betydning, eller et salt eller et reaktivt derivat derav, omsettes med et amin med den generelle formel 2 3in which X is halogen, R 2 and R 3 and A has the above meaning, or (b) a compound of the general formula in which Z, A and R 3 have the above meaning, or a salt or reactive derivative thereof, is reacted with an amine of the general formula 2 3 hvori R og R har den ovennevnte betydning, og om ønsket, for fremstilling av en forbindelse med den generelle formel hvori R 1 , R 2, Z, X, A og A<1> har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formelin which R and R have the above-mentioned meaning, and if desired, for the preparation of a compound of the general formula in which R 1 , R 2 , Z, X, A and A<1> have the above-mentioned meaning, an obtained compound is reacted with the general formula hvori R 1 , R 2, Z, A og A' har den ovennevnte betydning,'med etin which R 1 , R 2 , Z, A and A' have the above meaning,' with a halogeneringsmiddel, ellerhalogenating agent, or om ønsket, for fremstilling av en forbindelse med den generelle formelif desired, for the preparation of a compound of the general formula hvori R''', Z og A har den ovennevnte betydning og B er 2 7 8 hvori R har den ovennevnte betydning og R og R hver er hydrogen eller lavere alkyl, A<*>'' er lavere alkylen og R <9>er lavere alkanoyl, omsettes en erholdt forbindelse med den generelle formel hvori R<1>, Z, A, B og A1'1 har den ovennevnte betydning, med et alkanoyleringsmiddel, eller om ønsket,for fremstilling av en forbindelse med den generelle formel hvori X<1> er halogen og Z,A og R<*>" har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel hvori A, Z og R"<1>" har den ovennevnte betydning, med en hydrohalogensyre, ell er wherein R''', Z and A have the above meaning and B is 2 7 8 wherein R has the above meaning and R and R are each hydrogen or lower alkyl, A<*>'' is lower alkylene and R <9> is lower alkanoyl, an obtained compound of the general formula in which R<1>, Z, A, B and A1'1 have the above-mentioned meaning is reacted with an alkanoylating agent, or if desired, to produce a compound of the general formula in which X<1> is halogen and Z, A and R<*>" have the above meaning, a compound obtained with the general formula in which A, Z and R"<1>" has the above meaning is reacted with a hydrohalic acid, or is om ønsket, for fremstilling av en forbindelse med den generelle formelif desired, for the preparation of a compound of the general formula I45I45 hvori A, Z, R , R og R har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formelin which A, Z, R , R and R have the above meaning, a compound obtained is reacted with the general formula hvori A, Z og R<1> har den ovennevnte betydning, med et amin med den generelle formelwherein A, Z and R<1> have the above meaning, with an amine of the general formula hvori R<4> og R^ har den ovennevnte betydning, ellerwherein R<4> and R^ have the above meaning, or om ønsket, for fremstilling av en forbindelse med den generelle formel hvori A, Z, A'', R<1>, R^, R<4> og R^ har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel 1 2 hvori X<1>' er halogen og Z, A, A', R og R har den ovennevnte betydning, med et amin med den generelle formel 4 5 hvori R og R har den ovennevnte betydning, eller om ønsket, for fremstilling av en forbindelse med den generelle formel 6 V 8 hvori R er hydrogen eller lavere alkyl og Z, A, R , R og R har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel 17 8if desired, for the preparation of a compound of the general formula in which A, Z, A'', R<1>, R^, R<4> and R^ have the above meaning, an obtained compound of the general formula 1 is reacted 2 in which X<1>' is halogen and Z, A, A', R and R have the above meaning, with an amine of the general formula 4 5 in which R and R have the above meaning, or if desired, for the preparation of a compound of the general formula 6 V 8 in which R is hydrogen or lower alkyl and Z, A, R , R and R have the above meaning, an obtained compound of the general formula 17 8 is reacted hvori Z, A, R , R og R har den ovennevnte betydning, med et alkylenoksyd med den generelle formelwherein Z, A, R , R and R have the above meaning, with an alkylene oxide of the general formula hvori R har den ovennevnte betydning, ellerwherein R has the above meaning, or om ønsket, for fremstilling av en forbindelse med den generelle formel 17 8 hvori A'' er lavere alkylen, Z, A, R , R og R har den ovennevnte betydning, omsettes en erholdt forbindelse med den generelle formel 17 8 hvori Z, A, R , R og R har den ovennevnte betydning, med en haloalkanol med den generelle formel:if desired, for the preparation of a compound of the general formula 17 8 in which A'' is lower alkylene, Z, A, R , R and R have the above meaning, an obtained compound of the general formula 17 8 in which Z, A , R , R and R have the above meaning, with a haloalkanol of the general formula: hvori X''• er halogen og A'<1> har den ovennevnte.betydning, eller • om ønsket, for fremstilling av en forbindelse med den generellewherein X''• is halogen and A'<1> has the above meaning, or • if desired, for the preparation of a compound with the general formelformula hvori A<1>'<1> betyr lavere alkylen og R<1>^ alkyl, med tilsammen høyst 6 karbonatomer, og Z, A og R har den ovennevnte betydning, reduseres en erholdt forbindelse med den generelle formelin which A<1>'<1> means lower alkylene and R<1>^ alkyl, with a total of at most 6 carbon atoms, and Z, A and R have the above meaning, a compound obtained is reduced with the general formula hvori Z, A, A' ' • , R"*" og R"^ har den ovennevnte betydning, med et reduksjonsmiddel, ellerwherein Z, A, A' ' • , R"*" and R"^ have the above meaning, with a reducing agent, or om ønsket, for fremstilling av en forbindelse med den generelle formelif desired, for the preparation of a compound of the general formula hvori Z, A, A'<1>', B og R<1> har den ovennevnte betydning, reduseres en erholdt forbindelse med den generelle formelwherein Z, A, A'<1>', B and R<1> have the above meaning, a compound obtained is reduced by the general formula hvori R<11> er lavere alkyl og Z, A, A'* 1, B og R<1> har den ovennevntewherein R<11> is lower alkyl and Z, A, A'* 1, B and R<1> have the above betydning, med et reduksjonsmiddel.meaning, with a reducing agent.
NO3797/68A 1967-09-30 1968-09-26 NO133141C (en)

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