NO128822B - - Google Patents

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NO128822B
NO128822B NO100670A NO100670A NO128822B NO 128822 B NO128822 B NO 128822B NO 100670 A NO100670 A NO 100670A NO 100670 A NO100670 A NO 100670A NO 128822 B NO128822 B NO 128822B
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Norway
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compound
general formula
chloro
benzothiazolinone
piperazinyl
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NO100670A
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Norwegian (no)
Inventor
S Umio
I Ueda
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Fujisawa Pharmaceutical Co
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Publication of NO128822B publication Critical patent/NO128822B/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Description

Analogifremgangsmåte for fremstilling av Analogy method for the production of

nye, terapeutisk aktive acyloksyalkyl-heterocykliske forbindelser. new, therapeutically active acyloxyalkyl heterocyclic compounds.

Foreliggende oppfinnelse angår en analogi-fremgangsmåte for fremstilling av nye, terapeutisk aktive acyloksyalkyl-heterocykliske forbindelser med den generelle formel (i) hvori Z er svovel, oksygen eller lavere alkylimino, A er lavere alkylen, R^ er hydrogen, halogen eller trifluormetyl, R2 er acyl valgt fra gruppen bestående av hoyere alifatisk acyl, fenyl(lavere)alkanoyl og benzoyl, hvori fenyldelen kan være substituert med opp til 3 halogenatomer, lavere alkylgrupper og/eller lavere alkoksygrupper, eller syreaddisjonssalter derav, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at The present invention relates to an analogue method for the preparation of new, therapeutically active acyloxyalkyl heterocyclic compounds of the general formula (i) in which Z is sulphur, oxygen or lower alkylimino, A is lower alkylene, R^ is hydrogen, halogen or trifluoromethyl, R2 acyl is selected from the group consisting of higher aliphatic acyl, phenyl(lower)alkanoyl and benzoyl, in which the phenyl part may be substituted with up to 3 halogen atoms, lower alkyl groups and/or lower alkoxy groups, or acid addition salts thereof, and the peculiarity of the method according to the invention is that

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

hvori Z og har den ovennevnte betydning, eller dens metallsalt, omsettes med en karbamoylforbindelse med den generelle formel wherein Z and has the above meaning, or its metal salt, is reacted with a carbamoyl compound of the general formula

hvori X er en syrerest og A og R^ har den ovennevnte betydning, eller wherein X is an acid residue and A and R^ have the above meaning, or

b) en forbindelse med den generelle formel b) a compound with the general formula

hvori Z og har den ovennevnte betydning, eller dens reaktive wherein Z and have the above meaning, or their reactive

derivat omsettes med et amin med den generelle formel derivative is reacted with an amine of the general formula

hvori A og R2 har den ovennevnte betydning, eller et salt derav, eller wherein A and R 2 have the above meaning, or a salt thereof, or

c) en forbindelse med den generelle formel c) a compound with the general formula

hvori Z og har den ovennevnte betydning, omsettes med en wherein Z and has the above meaning, is replaced by a

acyloksyalkyl-forbindelse med den generelle formel acyloxyalkyl compound of the general formula

X-A-OR2X-A-OR2

hvori X, A og R2 har den ovennevnte betydning, eller wherein X, A and R 2 have the above meaning, or

d) en forbindelse med den generelle formel d) a compound with the general formula

hvori Z, A og R.^ har den ovennevnte betydning, eller et salt derav, omsettes med et acylerende middel med den generelle formel wherein Z, A and R.^ have the above meaning, or a salt thereof, is reacted with an acylating agent of the general formula

hvori har den ovennevnte betydning, eller dets reaktive derivat, hvoretter den resulterende forbindelse med formel I wherein it has the above meaning, or its reactive derivative, after which the resulting compound of formula I

om onskes omdannes til sitt syreaddisjonssalt. if desired is converted to its acid addition salt.

De i henhold til oppfinnelsen fremstillbare forbindelser har The compounds that can be prepared according to the invention have

i og for seg anti-inflammatoriske, antipyretiske og analgetiske virkninger, men har i tillegg dertil, <q>g i motsetning til nær beslektede forbindelser ikke noen bitter smak slik at de egner seg for oral tilfbrsel. in and of themselves anti-inflammatory, antipyretic and analgesic effects, but in addition, <q>g unlike closely related compounds, do not have a bitter taste so that they are suitable for oral administration.

Oppfinnelsen vil lettere kunne forstås ut fra den folgende detaljerte fremstilling av foretrukne utforelsesformer. The invention will be easier to understand from the following detailed presentation of preferred embodiments.

Forbindelsene med formel (I) kan fremstilles fra tilsvarende kondenserte heterocykliske utgangsforbindelser med den generelle formel (II) The compounds of formula (I) can be prepared from corresponding condensed heterocyclic starting compounds of the general formula (II)

hvori Z og har den ovenfor angitte betydning, wherein Z and have the above meaning,

henholdsvis fra den tilsvarende karboksylalkylforbindelse med den generelle formel (III) respectively from the corresponding carboxylalkyl compound of the general formula (III)

hvori Z og har den tidligere angitte betydning. henholdsvis fra den tilsvarende heterocykliske forbindelse med den generelle formel (IV) hvori Z og har den tidligere angitte betydning, henholdsvis fra den tilsvarende hydroksyalkylheterocykliske forbindelse med den generelle formel (V) wherein Z and have the previously indicated meaning. respectively from the corresponding heterocyclic compound of the general formula (IV) in which Z and have the previously stated meaning, respectively from the corresponding hydroxyalkylheterocyclic compound of the general formula (V)

hvori Z, A og R^ har den ovenfor angitte betydning. in which Z, A and R^ have the meaning given above.

Når utgangsforbindelsen er forbindelsen med (II) underkastes denne en N-substitusjon. N-substitusjonen kan gjennomfores ved å omsette forbindelsen rred formel (II) (J. Pharm. Soc. Japan, 77, 349 (1957) ) eller dens metallsalter (f.eks. natriumsaltene, kallimsaltene, kalsiumsaltene, etc.) med en karbamoylforbindelse med den generelle formel (VI) hvori X er en syrerest (f.eks. klor, brom, jod, metylsulfat, etylsulfat, benzensulfonat, toluensulfonat, metylkarbamat, etylkarbamat, etc. ) og A og har den ovenfor angitte betydning. When the starting compound is the compound with (II), this is subjected to an N-substitution. The N-substitution can be carried out by reacting the compound of formula (II) (J. Pharm. Soc. Japan, 77, 349 (1957) ) or its metal salts (e.g. the sodium salts, potassium salts, calcium salts, etc.) with a carbamoyl compound with the general formula (VI) in which X is an acid residue (e.g. chlorine, bromine, iodine, methyl sulfate, ethyl sulfate, benzene sulfonate, toluene sulfonate, methyl carbamate, ethyl carbamate, etc. ) and A and has the above meaning.

Omsetningen gjennomfores vanlig i et inert losningsmiddel som f.eks. benzen, toluen, eter, metanol, etanol, dimetylformamid, etc. Hvor forbindelsen med formel II anvendes som sådan er det onskelig å anvende et basisk kondenseringsmiddel, f.eks. alkali-hydroksyd som natriumhydroksyd, kaliumhydroksyd, etc, alkalikarbonat som f.eks. natriumkarbonat, kaliumkarbonat, etc, alkali-alkoksyd som f.eks. natriummetoksyd, natriumetoksyd, kalium-etoksyd, etc, alkalihydrid som f.eks. natriumhydrid, kalium-hydrid, etc, alkaliamid som f.eks. natriumamid, kaliumamid, litiumamid, etc, og lignende. Reaksjons tempera turen avhenger av utgangsforbindelsen med formel (II), reaksjonskomponenten med formel (VI), det basiske kondenseringsmiddel og det losningsmiddel som anvendes i praksis. The reaction is usually carried out in an inert solvent such as e.g. benzene, toluene, ether, methanol, ethanol, dimethylformamide, etc. Where the compound of formula II is used as such, it is desirable to use a basic condensing agent, e.g. alkali hydroxide such as sodium hydroxide, potassium hydroxide, etc., alkali carbonate such as e.g. sodium carbonate, potassium carbonate, etc., alkali alkoxide such as e.g. sodium methoxide, sodium ethoxide, potassium ethoxide, etc., alkali hydride such as sodium hydride, potassium hydride, etc., alkali amide such as sodium amide, potassium amide, lithium amide, etc, and the like. The reaction temperature depends on the starting compound of formula (II), the reaction component of formula (VI), the basic condensing agent and the solvent used in practice.

Når utgangsforbindelsen er forbindelsen med formel (III) underkastes denne en amidering. Amideringen kan gjennomfores ved å omsette forbindelsen med formel (III) (se britisk patentskrift nr. 862.226) eller dens reaktive derivat med et amin med den generelle formel (VII) When the starting compound is the compound of formula (III), this is subjected to an amidation. The amidation can be carried out by reacting the compound of formula (III) (see British Patent No. 862,226) or its reactive derivative with an amine of the general formula (VII)

hvori A og R2 har den ovenfor angitte betydning, eller et salt av denne som f.eks. hydrokloridet, hydrobromidet, sulfatet, picratet, tartratet, etc. in which A and R 2 have the above-mentioned meaning, or a salt thereof such as e.g. the hydrochloride, hydrobromide, sulphate, picrate, tartrate, etc.

Eksempler på reaktive derivater av forbindelsen med formel (III) er syrehalogenider som f.eks. syrekloridet, syrebromidet, etc., syreanhydrider som f.eks. alkylfosforsyreanhydrid, aromatiske karboksyl syr eanhydr ider, etc, videre syreamider som f. eks. syreamidet med imidazol, syreamidet med 4-substituert imidazol, etc, videre syreestere som f.eks. metylester, etylester, cyanometylester, p-nitrofenylester, etc, samt syreazidet. Examples of reactive derivatives of the compound with formula (III) are acid halides such as e.g. the acid chloride, the acid bromide, etc., acid anhydrides such as alkyl phosphoric anhydride, aromatic carboxylic acid anhydrides, etc., further acid amides such as the acid amide with imidazole, the acid amide with 4-substituted imidazole, etc., further acid esters such as e.g. methyl ester, ethyl ester, cyanomethyl ester, p-nitrophenyl ester, etc., as well as the acid azide.

Når forbindelsen med formel (III) anvendes som sådan er det vanlig nodvendig å anvende et kondenseringsmiddel. Eksempler på kondenseringsmidler er NjN^-dicykloheksylkarbodiimid, poly-fosforsyre, etylpolyfosfat, isopropylpolyfosfat, etc. When the compound of formula (III) is used as such, it is usually necessary to use a condensing agent. Examples of condensing agents are NjN^-dicyclohexylcarbodiimide, polyphosphoric acid, ethyl polyphosphate, isopropyl polyphosphate, etc.

Omsetningen gjennomfores vanlig i et inert løsningsmiddel som f.eks. aceton, dioksan, acetonitril, dimetylformamid, dimetylacetamid, dimetylsulfoksyd, kloroform, etylendiklorid, tetrahydro-furan, etylacetat, pyridin, etc. Om nodvendig kan en basisk substans som f.eks. alkalikarbonat, alkalihydrogenkarbonat, trialkylamin, pyridin, etc. være tilstede under omsetningen. Reaksjonstemperaturen varieres over et vidt område, men reaksjonen utfores vanlig under avkjoling eller ved romtemperatur. The reaction is usually carried out in an inert solvent such as e.g. acetone, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, chloroform, ethylene dichloride, tetrahydrofuran, ethyl acetate, pyridine, etc. If necessary, a basic substance such as e.g. alkali carbonate, alkali hydrogen carbonate, trialkylamine, pyridine, etc. be present during the turnover. The reaction temperature is varied over a wide range, but the reaction is usually carried out during cooling or at room temperature.

Når utgangsforbindelsen er forbindelsen med formel (IV) underkastes denne en N-acyloksyalkylering. N-acyloksyalkyleringen kan gjennomfores ved å omsette forbindelsen med formel (IV) When the starting compound is the compound of formula (IV), this is subjected to N-acyloxyalkylation. The N-acyloxyalkylation can be carried out by reacting the compound of formula (IV)

med acyloksyalkylforbindelsen med den generelle formd. (VIII) with the acyloxyalkyl compound of the general form. (VIII)

hvori X, A og R2 har den ovenfor angitte betydning. wherein X, A and R 2 have the meaning given above.

Forbindelsen med (IV) kan fremstilles ved å omsette den tilsvarende karboksylalkylforbindelse med formel (III) med piperazin (eller diazepin) i nærvær av det kondenseringsmiddel som er nevnt for den tidligere omtalte amidering. Omsetningen kan gjennomfores i et inert løsningsmiddel som f.eks. metanol, etanol, eter, benzen, aceton, dimetylformamid, dimetylsulfoksyd, etc. og om nodvendig i nærvær av det basiske kondenseringsmiddel som er nevnt for den tidligere omtalte N-substituering. Reaksjonstemperaturen avhenger av utgangsforbindelsen med formel (IV), reaksjonskomponenten med formel (VIII), det basiske kondenseringsmiddel og det løsningsmiddel som anvendes i praksis, idet reaksjonstemperaturen varieres fra romtemperatur til rundt koke-punktet for losningsmidlet. The compound with (IV) can be prepared by reacting the corresponding carboxylalkyl compound of formula (III) with piperazine (or diazepine) in the presence of the condensing agent mentioned for the previously mentioned amidation. The reaction can be carried out in an inert solvent such as e.g. methanol, ethanol, ether, benzene, acetone, dimethylformamide, dimethylsulfoxide, etc. and if necessary in the presence of the basic condensing agent mentioned for the previously mentioned N-substitution. The reaction temperature depends on the starting compound of formula (IV), the reaction component of formula (VIII), the basic condensing agent and the solvent used in practice, the reaction temperature being varied from room temperature to around the boiling point of the solvent.

Når utgangsforbindelsen er forbindelsen med formel (V) underkastes denne en acylering. Acyleringen kan gjennomfores ved å omsette forbindelsen med formel (V) eller et salt derav som f .eks. hydrokloridet,' hydrobromidet, sulfatet, acetatet, picratet, citratet, tartratet, etc. med et acyleringsmiddel med den generelle formel (IX) When the starting compound is the compound of formula (V), this is subjected to an acylation. The acylation can be carried out by reacting the compound of formula (V) or a salt thereof such as, e.g. the hydrochloride, the hydrobromide, the sulfate, the acetate, the picrate, the citrate, the tartrate, etc. with an acylating agent of the general formula (IX)

hvori R2 har den ovenfor angitte betydning, eller dens reaktive derivater. Forbindelsen med formel (V) er ny og kan fremstilles ved å omsette den tilsvarende kondenserte heterocykliske forbindelse med formel (II) med en 4-hydroksyalkyl-l-piperazinyl(eller diazepinyl)karbonylalkylforbindelse med den generelle formel wherein R 2 has the above meaning, or its reactive derivatives. The compound of formula (V) is new and can be prepared by reacting the corresponding condensed heterocyclic compound of formula (II) with a 4-hydroxyalkyl-1-piperazinyl (or diazepinyl)carbonylalkyl compound of the general formula

hvori X og A har den tidligere angitte betydning, i nærvær av et basisk kondensasjonsmiddel. wherein X and A are as previously defined, in the presence of a basic condensing agent.

Eksempler på reaktive derivater av forbindelsen med formel (IX) er syrehalogenider, syreanhydrider, syreamider, syreestere og syreazider som nærmere angitt under avsnittet om amideringen. Når forbindelsen med formel (IX) anvendes som sådan er det vanlig nodvendig å anvende et kondenseringsmiddel som også er omhandlet under avsnittet om amidering. Omsetningen gjennomfores vanlig i et inert løsningsmiddel som f.eks. aceton, dioksan, acetonitril, dimetylformamid, dimetylacetamid, dimetylsulfoksyd, kloroform, etylendiklorid, tetra-hydrofuran, etylacetat, pyridin, etc. Reaksjonstemperaturen kan varieres over et vidt område og avhenger av utgangsforbindelsen med formel (V) reaksjonskomponenten med formel (IX), kondenseringsmidlet og det løsningsmiddel som anvendes i praksis. Examples of reactive derivatives of the compound of formula (IX) are acid halides, acid anhydrides, acid amides, acid esters and acid azides as specified in more detail under the section on amidation. When the compound of formula (IX) is used as such, it is usually necessary to use a condensing agent which is also discussed under the section on amidation. The reaction is usually carried out in an inert solvent such as e.g. acetone, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, chloroform, ethylene dichloride, tetrahydrofuran, ethyl acetate, pyridine, etc. The reaction temperature can be varied over a wide range and depends on the starting compound of formula (V), the reaction component of formula (IX), the condensing agent and the solvent used in practice.

Som tidligere angitt er forbindelsene med formel (I) i og for As previously indicated, the compounds of formula (I) are in and for

seg nyttige som anti-inflammatoriske midler. Noen av de prøveresultater som viser deres brukbarhet er vist i det folgende, men som nevnt er en særegen og spesiell fordel ved forbindelsene med formel I at de ikke har bitter smak slik at de er egnet for oral tilforsel. useful as anti-inflammatory agents. Some of the test results showing their utility are shown below, but as mentioned, a distinctive and special advantage of the compounds of formula I is that they do not have a bitter taste so that they are suitable for oral administration.

Den inhiberende effekt på svelling indusert ved hjelp av albumin eller carragenin er sammenlignet ut fra sammenligningsforbindelsen 3-/4-(2-palmitoyloksyetyl)-l-piperazinyl/karbonyl-metyl-5-klor-2-benzo-tiazolinon. The inhibitory effect on swelling induced by means of albumin or carrageenan is compared on the basis of the comparison compound 3-/4-(2-palmitoyloxyethyl)-1-piperazinyl/carbonyl-methyl-5-chloro-2-benzo-thiazolinone.

Metodikk: Methodology:

Hanrotter av Wistar-stammen som hver veide 150 til 200 g ble oppdelt i to grupper. En gruppe (10 rotter) mottok oralt 1 cc av en suspensjon av proveforbindelsen i 1% karboksymetyl-celluloseopplosning pr. 100 g kroppsvekt (provegruppen), og den annen gruppe (10 rotter) mottok 1 cc av 1% karboksymetyl-ceulluloseopplosning alene pr. 100 g kroppsvekt på lignende måte (kontrollgruppen). 1 time etter tilforsel ble eggehvitealbumin (1094, 0,1 ml) eller corragenin (1%, 0,1 ml) gitt til dyrene i deres bakpoter for å indusere svelling. Potetykkelsen ble målt ved hjelp av skyvelær ved forskjellige tidspunkt etter injeksjon av den svelling-induserende substans. Svellingsprosent og inhiberende prosent av svellingen ble beregnet fra folgende ligninger: Male Wistar rats each weighing 150 to 200 g were divided into two groups. One group (10 rats) orally received 1 cc of a suspension of the test compound in 1% carboxymethyl cellulose solution per 100 g body weight (test group), and the other group (10 rats) received 1 cc of 1% carboxymethyl cellulose solution alone per 100 g body weight in a similar way (control group). 1 h after gavage, egg white albumin (1094, 0.1 ml) or corragenin (1%, 0.1 ml) was administered to the animals in their hind paws to induce swelling. Paw thickness was measured using calipers at various times after injection of the swelling-inducing substance. Swelling percentage and inhibitory percentage of swelling were calculated from the following equations:

T: Potetykkelse for tilforsel av den svelle-induserende T: Paw thickness for supplying the swelling-inducing agent

substans. substance.

t: Potetykkelse ved forskjellige tidspunkt etter at den t: Paw thickness at different times after the

svelle-induserende substans var tilfort. swelling-inducing substance was added.

C: Svelle-^ i kontrollgruppen. C: Swell-^ in the control group.

D: Svelle-/? i provegruppen. D: Swell-/? in the sample group.

Flere timer etter injeksjon av den svelle-induserende substans (3 timer for albumin-injeksjonen og h timer for carrageenin-injeksjonen) ble dyrene drept. Begge baklabber ble kuttet av og veiet. Svellings-$ og inhiberende % for svellingen ble beregnet fra folgende ligninger: Several hours after injection of the swelling-inducing substance (3 hours for the albumin injection and h hours for the carrageenin injection), the animals were killed. Both hind paws were cut off and weighed. Swelling-$ and inhibitory % for the swelling were calculated from the following equations:

W: Vekt av den pote som ikke var injisert med svelle-induserende substans. W: Weight of the paw that was not injected with swelling-inducing substance.

w: Vekt av den pote som var injisert med svelle-induserende w: Weight of the paw injected with the swelling inducer

substans. substance.

E: Svelle-^ for kontrollgruppe. E: Swell-^ for control group.

F: Svellefor behandlet gruppe. F: Swelling for treated group.

Resultater; Results;

Resultatene er vist i de folgende tabeller 1 og 2. The results are shown in the following tables 1 and 2.

Forbindelsen med formel (I) fremstilt i henhold til oppfinnelsen kan omdannes til et syreaddisjonssalt som f.eks. hydrokloridet, hydrobromidet, hydrojodidet, nitratet, fosfatet, sulfatet, acetatet, citratet, tartratet, laktatet, etc. The compound of formula (I) produced according to the invention can be converted into an acid addition salt such as, for example the hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, acetate, citrate, tartrate, lactate, etc.

Forbindelsen med formel (I) har antipyretiske og analgetiske egenskaper ved siden av anti-inflammatorisk aktivitet. Blant utgangsforbindelsene for fremstilling av forbindelsen med formel (I) fremviser forbindelsen- med formel (V) samme kraftige farmasøytiske aktivitet. Forbindelsen med formel (V) har imidlertid en bitter smak hvilket ikke passer for farmasøytiske preparater for oral tilforsel som f.eks. pulver, granuler, piller, The compound of formula (I) has antipyretic and analgesic properties in addition to anti-inflammatory activity. Among the starting compounds for the preparation of the compound of formula (I), the compound of formula (V) exhibits the same powerful pharmaceutical activity. However, the compound of formula (V) has a bitter taste which is not suitable for pharmaceutical preparations for oral administration such as e.g. powders, granules, pills,

eliksir, sirup, emulsjoner, etc. Den bitre smak for forbindelsen med formel (V) kunne fjernes uten nedsettelse av den farmasøytiske effekt ved hjelp av omdannelsen til forbindelse med formel (I), hvori hydroksygruppen i forbindelsen med formel (V) er dekket av acylgruppen. elixir, syrup, emulsions, etc. The bitter taste of the compound of formula (V) could be removed without reducing the pharmaceutical effect by means of the conversion to the compound of formula (I), in which the hydroxy group of the compound of formula (V) is covered by the acyl group.

Forbindelsene med formel (I) er brukbare for behandling av feber, smerter og inflammatoriske tilstander forbundet med smerter, feber, skjelving og/eller svelling. The compounds of formula (I) are useful for the treatment of fever, pain and inflammatory conditions associated with pain, fever, chills and/or swelling.

Forbindelsen med formel (I) kan tilfores ved vanlige metoder, The compound of formula (I) can be supplied by usual methods,

med vanlige typer av énhetsdose eller med vanlige farmasoytiske bærere for å frembringe anti-inflammatoriske, inpyretiske og analgetiske virkninger i dyr og mennesker. Forbindelsene kan således anvendes i form av farmasoytiske preparater, som er tilblandet en farmasøytisk tålbar organisk eller uorganisk bærer passende for enteral, parenteral eller lokal tilforsel. Oral tilforsel ved bruk av pulveret, tabletter, kapsler eller i flytende former som f.eks. suspensjoner, opplbsninger eller emulsjoner er særlig fordelaktig . Når forbindelsene tildannes til tabletter kan de vanlige bindemidler og opplosningsfremmende midler anvendes i de terapeutiske enhetsdoser. with common types of unit dose or with common pharmaceutical carriers to produce anti-inflammatory, antipyretic and analgesic effects in animals and humans. The compounds can thus be used in the form of pharmaceutical preparations, which are mixed with a pharmaceutically acceptable organic or inorganic carrier suitable for enteral, parenteral or local administration. Oral administration using the powder, tablets, capsules or in liquid forms such as e.g. suspensions, solutions or emulsions are particularly advantageous. When the compounds are formed into tablets, the usual binding agents and dissolution promoting agents can be used in the therapeutic unit doses.

Som eksempler på bindemidler kan nevnes glukose, laktose, gummi-arabikum, gelatin, mannitol, stivelsespasta, magnesiumtrisilikat og talkum. Som eksempler på lbsningsfremmende midler kan nevnes kornstivelse, keratin, kolloidal silisiumoksyd og potetstivelse. Når de tilfores som væsker kan vanlige flytende bærere anvendes. Examples of binders include glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate and talc. Cereal starch, keratin, colloidal silicon oxide and potato starch can be mentioned as examples of loosening-promoting agents. When supplied as liquids, ordinary liquid carriers can be used.

Enhetsdoseringen for terapeutisk virksomme mengder av forbindelsen med formel (I) for terapeutisk bruk for mennesker varierer innen vide grenser slik at den ovre grense bare bestemmes av den onskede virkning og økonomiske betraktninger. Videre kan selvfolgelig doseringen for det anvendte terapeutiske middel variere betraktelig etter alder for pasienten og graden av onsket terapeutisk virkning. Hver énhetsdose kan gjerne inneholde fra 5 til 95 % av de nye terapeutisk aktive forbindelser idet resten da utgjor vanlige farmasøytiske bærere. Med farmasoytiske bærere menes ikke terapeutisk virksomme materialer som vanlig anvendes med enhetsdoser og disse omfatter da fyllstoffer, fortynnings-midler, bindemidler, smoremidler, opplosningsfremmende midler og løsningsmidler. Det er også selvfolgelig mulig å tilfore forbindelsene, dvs. de rene sådanne, uten bruk av noen farmasøytisk bærer. The unit dosage for therapeutically effective amounts of the compound of formula (I) for human therapeutic use varies within wide limits so that the upper limit is determined only by the desired effect and economic considerations. Furthermore, of course, the dosage for the therapeutic agent used can vary considerably according to the age of the patient and the degree of desired therapeutic effect. Each unit dose may preferably contain from 5 to 95% of the new therapeutically active compounds, with the remainder then constituting ordinary pharmaceutical carriers. Pharmaceutical carriers do not mean therapeutically effective materials that are usually used in unit doses and these then include fillers, diluents, binders, lubricants, dissolution promoting agents and solvents. It is also, of course, possible to administer the compounds, i.e. the pure ones, without the use of any pharmaceutical carrier.

Praktiske og foretrukne utforelsesformer for fremgangsmåten i henhold til oppfinnelsen er detaljert i de folgende utforelseseksempler. Practical and preferred embodiments of the method according to the invention are detailed in the following embodiment examples.

Eksempel 1 Example 1

(1) En lbsning av 3-/ti-(2-hydroksyetyl)-1 -piperazinyl7karbonyl-metyl-5-klor-2-benzotiazolinon (15,0 g) og trietylamin (16,6 g) (1) A solution of 3-[ti-(2-hydroxyethyl)-1-piperazinyl-7-carbonyl-methyl-5-chloro-2-benzothiazolinone (15.0 g) and triethylamine (16.6 g)

i torr kloroform (330 cc) ble holdt ved 20°C og en losning av palmitoylklorid (3<*>+,7 g) i torr kloroform (60 cc) ble tilsatt dråpevis dertil under omroring i lopet av 2 timer. Blandingen ble videre omrort i 3 timer og etter fullendt omsetning ble det tilsatt 10$ vandig natriumhydroksylosning • (100 cc) og vann (100 cc). Kloroformskiktet ble fraskilt, vasket tre ganger med vann og så torret over vannfritt magnesiumsulfat. Losningsmidlet ble avdestillert og den derved oppnådde rest ble krystallisert fra en blanding av benzen og petroleter og ga 3-/t|~(2-palmitoyloksyetyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon (1<l>+j5 g) som farvelose flak med smeltepunkt 8k til 86°C. in dry chloroform (330 cc) was kept at 20°C and a solution of palmitoyl chloride (3<*>+.7 g) in dry chloroform (60 cc) was added dropwise thereto with stirring over 2 hours. The mixture was further stirred for 3 hours and, after complete reaction, 10% aqueous sodium hydroxide solution • (100 cc) and water (100 cc) were added. The chloroform layer was separated, washed three times with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was crystallized from a mixture of benzene and petroleum ether to give 3-[t|~(2-palmitoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone (1<l>+j5 g ) as colorless flakes with melting point 8k to 86°C.

(2) En opplbsning av 3-^+-( 2-hydroksypropyl)-1 -piperazinyU-karbonylmetyl-5-klor-2-benzotiazolinon (2,0 g) og trietylamin (1,1 g) i torr kloroform (20 cc) ble holdt ved 15 til 20°C under omroring. En opplosning av palmitoylklorid (5»9 g) i torr kloroform (10 cc) ble tilsatt dråpevis i lopet av <*>+0 min. og blandingen ble omrort videre i Hr time. Etter avsluttet omsetning ble vann tilsatt til reaksjonsblandingen. Kloroformskiktet ble fraskilt, vasket med en vandig natriumkarbonatlosning tre ganger og deretter med vann og torret over vannfritt magnesiumsulfat. Losningsmidlet ble avdestillert og resten ble kromatografert på aluminiumoksyd under anvendelse av etylacetat som fremkaller. Den oppnådde utstromning ble inndampet og ga 3-/<*>*--(2-palmitoyloksy-propyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon (2) A solution of 3-^+-(2-hydroxypropyl)-1-piperazinyl-carbonylmethyl-5-chloro-2-benzothiazolinone (2.0 g) and triethylamine (1.1 g) in dry chloroform (20 cc ) was kept at 15 to 20°C with stirring. A solution of palmitoyl chloride (5.9 g) in dry chloroform (10 cc) was added dropwise over <*>+0 min. and the mixture was stirred further for Hr hour. After completion of the reaction, water was added to the reaction mixture. The chloroform layer was separated, washed with an aqueous sodium carbonate solution three times and then with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was chromatographed on alumina using ethyl acetate as developer. The resulting effluent was evaporated to give 3-[<*>*-(2-palmitoyloxy-propyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone

(0)9 g). Denne substans ble omkrystallisert fra blandingen av petroleter og benzen og ga et farvelost pulver med smeltepunkt 9h til 95°C. (0)9g). This substance was recrystallized from the mixture of petroleum ether and benzene and gave a colorless powder with a melting point of 9h at 95°C.

(3) En opplosning av 3-/^-( 2-hydroksyetyl)-1-pit>erazinyl7-karbonylmetyl-5-klor-2-benzotiazolinon (5,0 g) og vannfritt kaliumkarbonat (3*89 g) i torr kloroform (100 cc) ble holdt ved (3) A solution of 3-[^-(2-hydroxyethyl)-1-pit>erazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone (5.0 g) and anhydrous potassium carbonate (3*89 g) in dry chloroform (100 cc) was kept at

o o

20 til 23 C under roring og en opplosning av stearoylklorid (17,1 g) i torr kloroform (20 cc) ble tilsatt dråpevis dertil i lopet av 55 min. Blandingen ble omrort i 7 timer under omroring og etter avsluttet omsetning ble kloroformskiktet fraseparert, vasket med vann og så torret over vannfritt magnesiumsulfat. Losningsmidlet ble avdestillert under redusert trykk og ga en olje (8,3 g). Benzenlbsningen av oljen ble underkastet en kromatografering på en aluminiumoksydklonne og ga en olje (5,9 g). Den således oppnådde olje ble krystallisert og krystallene omkrystallisert fra petroleter f ire ganger og ga (2-stearoyloksyetyl) - 1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon som farvelose voksaktige krystaller med smp. 7^ til 76°C. 20 to 23 C with stirring and a solution of stearoyl chloride (17.1 g) in dry chloroform (20 cc) was added dropwise thereto over 55 min. The mixture was stirred for 7 hours with stirring and after completion of the reaction the chloroform layer was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oil (8.3 g). The benzene solution of the oil was chromatographed on an alumina column to give an oil (5.9 g). The oil thus obtained was crystallized and the crystals recrystallized from petroleum ether four times to give (2-stearoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone as colorless waxy crystals with m.p. 7^ to 76°C.

(<*>f) En opplosning av 3-ZIi—(2-hydroksyetyl)-1 -piperazinyl7-karbonylmetyl-5-klor-2-benzotiazolinon (20,0 g) og pyridin (8,85 g) i torr kloroform (250 cc) ble holdt ved 15 til 2Q°C under omroring. En opplosning av fenylacetyl-klorid Q+,7 g) i torr kloroform (<*>f) A solution of 3-ZIi-(2-hydroxyethyl)-1-piperazinyl7-carbonylmethyl-5-chloro-2-benzothiazolinone (20.0 g) and pyridine (8.85 g) in dry chloroform ( 250 cc) was maintained at 15 to 20°C with stirring. A solution of phenylacetyl chloride Q+.7 g) in dry chloroform

(30 cc) ble tilsatt dråpevis i lopet av 1 time og blandingen ble omrort i 3,1 time ved romtemperatur. Etter avsluttet omsetning ble en vandig natriumkarbonatopplosning tilsatt til reaksjonsblandingen. Kloroformskiktet ble fraskilt, vasket med natriumkarbonat og ekstrahert med 10$ saltsyre. Saltsyreskiktet ble satt bort over natten og utskilte krystaller ble samlet ved filtrering og så omkrystallisert fra etanol og ga 3-/<1>+-(2-fenyl-acetoksyetyl)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinonr-hydroklorid som farvelose; flak med smp. 206 til 207°C. (30 cc) was added dropwise over 1 hour and the mixture was stirred for 3.1 hours at room temperature. After completion of the reaction, an aqueous sodium carbonate solution was added to the reaction mixture. The chloroform layer was separated, washed with sodium carbonate and extracted with 10% hydrochloric acid. The hydrochloric acid layer was set aside overnight and precipitated crystals were collected by filtration and then recrystallized from ethanol to give 3-/<1>+-(2-phenyl-acetoxyethyl)-1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone n-hydrochloride as goodbye; flake with m.p. 206 to 207°C.

(5) En blanding av 3-/ J+-(2-hydroksypropyl)-1 -piperazinyl7-karbonylmetyl-5-klor-2-benzotiazolinon (2,0 g) og trietylamin (0,55 g) i torr kloroform (20 cc) ble holdt ved 20 til 25°C under omroring. En opplosning av fenylacetylklorid (1,01 g) i torr kloroform (10 cc) ble tilsatt dråpevis dertil og blandingen ble omrort i h timer ved romtemperatur. Etter avsluttet omsetning ble vann tilsatt til reaksjonsblandingen. Kloroformskiktet ble fraskilt, vasket med fortynnet natriumhydroksyd, vann, fortynnet saltsyre og vann i den angitte rekkefolge og torret over vannfritt (5) A mixture of 3-(J+-(2-hydroxypropyl)-1-piperazinyl7-carbonylmethyl-5-chloro-2-benzothiazolinone (2.0 g) and triethylamine (0.55 g) in dry chloroform (20 cc ) was kept at 20 to 25°C with stirring. A solution of phenylacetyl chloride (1.01 g) in dry chloroform (10 cc) was added dropwise thereto and the mixture was stirred for h hours at room temperature. After completion of the reaction, water was added to the reaction mixture. The chloroform layer was separated, washed with dilute sodium hydroxide, water, dilute hydrochloric acid and water in the order indicated and dried over anhydrous

l l

magnesiumsulfat. Losningsmidlet ble avdestillert og den resterende olje ble underkastet kromatografering med benzen på magnesium sulfate. The solvent was distilled off and the remaining oil was subjected to chromatography with benzene on it

en aluminiumoksydkolonne. Utstrømningen ble inndampet til en olje ( 0, h g) og etanolisk saltsyre ble tilsatt. Utskilte krystaller ble isolert ved filtrering og omkrystallisert fra vandig etanol-opplbsning og ga 2-f enylacetoksypropyl) -1 -piperazinyl7-karbonylmetyl-5-klor-2-benzotiazolinon-hydroklorid som et farvelost pulver med smp. 250°C (spalting). (6) En blanding av 3-/*i—(2-hydroksyetyl)-1 -piperazinyl7-karbonylmetyl-5-klor-2-benzotiazolinon (1,0 g), 3^,5-trimetoksy-benzoylklorid (0,7 g) og vannfritt kaliumkarbonat (2,0 g) i dimetylformamid (20 cc) ble omrort ved romtemperatur i 17 timer. Etter avslutet omsetning ble reaksjonsblandingen helt ut i vann og ekstrahert med kloroform. Ekstrakten ble torret og losningsmidlet avdestillert og resten kromatografert på aluminiumoksyd under anvendelse av etylacetat som fremkaller. Den oppnådde utstromning ble inndampet og resten ble opplost i en liten mengde torr etanol og ble omsatt til et fast stoff ved tilsetning av en eteropplosning av maleinsyre. Utskilte krystaller ble omkrystallisert fra torr etanol og ga 3-Z<1>+-(2-(3,<l>f,5-trimetoksybenzoyloksy)-etyl)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzo-tiazolinon-maleat (0,3 g) med smp. 123 "til 130°C (spalting). (7) En blanding av 3-/If-(2-hydroksyetyl)-1-piperazinyXfearbonyl-metyl-5-klor-2-benzokazolinon (1,0 g) palmitoyl-klorid (0,89 g), kaliumkarbonat (0,^-1 g) og tort dimetylformamid (0,5 cc) ble omrort i 3 timer. Etter avsluttet omsetning ble etylacetat og vann tilsatt reaksjonsblandingen. Etylacetatdelen ble vasket med vann og torret over vannfritt magnesiumsulfat. Losningsmidlet ble fjernet ved destillasjon og ga 3-/*(--(2-palmitoyloksye tyl )-1 - piperazinyl7karbonylmetyl-5-klor-2-benzoksazolinon (1,2 g). an alumina column. The effluent was evaporated to an oil (0.0 g) and ethanolic hydrochloric acid was added. Precipitated crystals were isolated by filtration and recrystallized from aqueous ethanol solution to give 2-phenylacetoxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone hydrochloride as a colorless powder m.p. 250°C (decomposition). (6) A mixture of 3-(1-(2-hydroxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone (1.0 g), 3,5-trimethoxy-benzoyl chloride (0.7 g) and anhydrous potassium carbonate (2.0 g) in dimethylformamide (20 cc) was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was dried and the solvent distilled off and the residue chromatographed on alumina using ethyl acetate as developer. The resulting effluent was evaporated and the residue was dissolved in a small amount of dry ethanol and converted to a solid by the addition of an ethereal solution of maleic acid. Crystals separated were recrystallized from dry ethanol to give 3-Z<1>+-(2-(3,<l>f,5-trimethoxybenzoyloxy)-ethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzo-thiazolinone- maleate (0.3 g) with m.p. 123" to 130°C (decomposition). (7) A mixture of 3-/If-(2-hydroxyethyl)-1-piperazinyXfearbonyl-methyl-5-chloro-2-benzocasazolinone (1.0 g) palmitoyl chloride ( 0.89 g), potassium carbonate (0.^-1 g) and dry dimethylformamide (0.5 cc) were stirred for 3 hours. After completion of the reaction, ethyl acetate and water were added to the reaction mixture. The ethyl acetate portion was washed with water and dried over anhydrous magnesium sulfate The solvent was removed by distillation to give 3-(--(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone (1.2 g).

Denne substans ble omkrystallisert fra pertroleter og ga et farvelost pulver med smp. 72 til 7<l>f°C. This substance was recrystallized from pertrol ether and gave a colorless powder with m.p. 72 to 7<l>f°C.

(8) Til en opplosning av 3-metyl-6-klor-1 -/*+-(2-hydroksyetyl)-1 - piperazinyl7karbonylmetyl-2-benzimidazolinon (0,35 g) i dimetylacetamid (7 cc) ble tilsatt kaliumkarbonat (0,3 g). Til blandingen ble ytterligere tilsatt en lbsning av palmitoylklorid (8) To a solution of 3-methyl-6-chloro-1 -/*+-(2-hydroxyethyl)-1-piperazinyl7carbonylmethyl-2-benzimidazolinone (0.35 g) in dimethylacetamide (7 cc) was added potassium carbonate ( 0.3g). A solution of palmitoyl chloride was further added to the mixture

(0,3 g) i dimetylformamid (3 cc). Den således oppnådde blanding ble omrort i 2 timer ved romtemperatur. Etter avsluttet omsetning ble reaksjonsblandingen helt ut på isblandet vann og ekstrahert med etylacetat flere ganger. Ekstraktan ble grundig vasket med vann og torret. Losningsmidlet ble fjernet ved destillasjon og resten ble omkrystallisert fra en blanding av benzen og en heksan og ga 3-metyl-6-klor-1 -Ztt—(2-palmitoyloksyetyl) -1 -piperazinyl7-karbonylmetyl-2-benzimidazolinon (0,25 g) med smp. 97 til 98°C. (9) 3-Zt(—(2-lauroyloksyabyl)-1 -piperazinyl7-karbonylmetyl-5-klor-2-benzotiazolinon (0,5 g) ble fremstilt som en olje på omtrent samme måte som ovenfor ved å omsette -3/**~(2-hydroksyetyl) -1 - piperazinyl7karbonylmetyl-5-klor-2-benzotia.zolinon (0,72 g) med lauroyl-klorid (0,^ g). Denne substans ble på konvensjonell måte omdannet til maleatet i form av farvelose krystaller med smp. 168 til 171°C. (10) 3-/tt—( 2-linoloyloksyetyl) -1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon (0,5 g) ble fremstilt i form av en olje på omtrent samme måte som ovenfor ved å omsette 3-/If-(2-hydroksy-etyl)-1--piperazinyl7karbpnylmetyl-5-klor-2-benzotiazolinon (0,7^ g) med linoloyl-klorid (0,8 g). Maleatet besto av farvelose krystaller med smp. 150 til 152°C (spalting). (11) 3-/5+-(2-lauroyloksypropyl)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon (0,8 g) ble fremstilt i form av en olje på omtrent samme'måte som ovenfor med å omsette 2-hydroksy-propyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon (0,9 g) med lauroyl-klorid (0<J>,6V g). Maleatet hadde smp. 162 til 165°C (12) 3-/th-(2-linoloyloksypropyl)-1 -piperazinyi/karbonylmetyl-5-klor-2-benzotiazolinon ble fremstilt i form av en olje på omtrent samme måte som ovenfor ved å omsette 3-/^^2-hydroksyprppyl) - 1^piperazinyi7-karbonylmetyl-5-klor-2-benzotiazolinon (0,9 g) (0.3 g) in dimethylformamide (3 cc). The mixture thus obtained was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was poured onto ice-mixed water and extracted with ethyl acetate several times. The extract was thoroughly washed with water and dried. The solvent was removed by distillation and the residue was recrystallized from a mixture of benzene and a hexane to give 3-methyl-6-chloro-1-Ztt-(2-palmitoyloxyethyl)-1-piperazinyl7-carbonylmethyl-2-benzimidazolinone (0.25 g) with m.p. 97 to 98°C. (9) 3-Zt(—(2-lauroyloxyabyl)-1-piperazinyl7-carbonylmethyl-5-chloro-2-benzothiazolinone (0.5 g) was prepared as an oil in much the same manner as above by reacting -3/ **~(2-Hydroxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothia.zolinone (0.72 g) with lauroyl chloride (0.^ g). This substance was conventionally converted to the maleate in the form of colorless crystals, mp 168 to 171° C. (10) 3-[tt-(2-linoloyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone (0.5 g) was prepared as an oil in much the same manner as above by reacting 3-(If-(2-hydroxy-ethyl)-1-piperazinyl-7-carbpnylmethyl-5-chloro-2-benzothiazolinone (0.7^ g) with linoloyl chloride (0.8 g ). The maleate consisted of colorless crystals with m.p. 150 to 152°C (dec.). (11) 3-(5+-(2-lauroyloxypropyl)-1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone (0.8 g ) was prepared in the form of an oil in much the same manner as above by reacting 2-hydroxy-propyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-b enzothiazolinone (0.9 g) with lauroyl chloride (0<J>.6V g). The maleate had m.p. 162 to 165 °C (12) 3-[th-(2-linoloyloxypropyl)-1-piperazinyi/carbonylmethyl-5-chloro-2-benzothiazolinone was prepared in the form of an oil in much the same manner as above by reacting 3- /^^2-Hydroxypropyl)-1^piperazinyi7-carbonylmethyl-5-chloro-2-benzothiazolinone (0.9 g)

med linoloylklorid (0,8 g),. Maleatet besto av farvelose krystaller med smp. 1^-7 til lk9°C (spalting). with linoleyl chloride (0.8 g),. The maleate consisted of colorless crystals with m.p. 1^-7 to lk9°C (cleavage).

(13) 3-A-(2-palmitoyloksyetyl)-1 -<p>i<p>erazin<y>l7karbonylmetyl-5-trifluormetyl-2-benzotiazolinon (1,3 g) i form av farvelose krystaller med smp. 98 til 99 C etter omkrystallisering 'fra petroleter ble fremstilt ved å omsette 3-/'+-(2-hydroksyetyl)-1 - piperazinyl7karbonylmetyl-5-trifluormetyl-2-benzotiazolinon (13) 3-A-(2-palmitoyloxyethyl)-1-<p>i<p>erazine<y>l7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone (1.3 g) in the form of colorless crystals with m.p. 98 to 99 C after recrystallization 'from petroleum ether was prepared by reacting 3-/'+-(2-hydroxyethyl)-1-piperazinyl7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone

(1,5 g) med palmitoylklorid (0,71 g). (1.5 g) with palmitoyl chloride (0.71 g).

(1^) 3-/5+-(2-stearoyloksyetyl)-1 -piperazinyl7karbonylmetyl-5-trifluormetyl-2-benzotiazolinon (1,5 g) i form av farvelose krystaller med smp. 95 til 96°C omkrystallisert fra etylacetat ble fremstilt ved å omsette 3-/I<—( 2-hydroksyetyl)-1 -piperazinyl7-karbonylmetyl-5-trifluormetyl-2-benzotiazolinon (1,0 g) med stearoyl-klorid (0,78 g). (1^) 3-(5+-(2-stearoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone (1.5 g) in the form of colorless crystals with m.p. 95 to 96°C recrystallized from ethyl acetate was prepared by reacting 3-(1<-(2-hydroxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone (1.0 g) with stearoyl chloride (0 .78 g).

Eksempel 2 Example 2

(1) Til en losning av 3-0-piperazinyl-karbonylmetyl)-5-klor-2-benzotiazolinon (1,5 g) i dimetylformamid (15 cc) tilsettes en losning av 2-palmitoyloksyetyl-bromid (1,8 g) og kaliumkarbonat (1,5 g) i dimetylformamid (5 cc) og blandingen omrbres i ho timer ved romtemperatur. Reaksjonsblandingen helles ut på isblandet vann og ekstraheres gjentatte ganger med etylacetat. Etylacetat-skiktet vaskes med vann og tbrres over vannfritt magnesiumsulfat. Losningsmidlet" avdestilleres og resten opplbses i etylacetat og kromatograferes på aluminiumoksyd under anvendelse av etylacetat som fremkaller. Således oppnådd utstrbmning ble inndampet og ga 3-/Tf—(2-palmitoyloksyetyl)-1 -piperazinyl/karbonylmetyl-5-klor-2-benzotiazolinon. Substansen ble omkrystallisert fra en blanding av petroleter og benzen og gir farvelose flak med smp. Bh til 86°C. (1) To a solution of 3-O-piperazinylcarbonylmethyl)-5-chloro-2-benzothiazolinone (1.5 g) in dimethylformamide (15 cc) is added a solution of 2-palmitoyloxyethyl bromide (1.8 g) and potassium carbonate (1.5 g) in dimethylformamide (5 cc) and the mixture is stirred for several hours at room temperature. The reaction mixture is poured onto ice-cold water and extracted repeatedly with ethyl acetate. The ethyl acetate layer is washed with water and passed over anhydrous magnesium sulfate. The solvent" is distilled off and the residue is dissolved in ethyl acetate and chromatographed on alumina using ethyl acetate as the developer. The residue thus obtained was evaporated to give 3-(Tf-(2-palmitoyloxyethyl)-1-piperazinyl/carbonylmethyl-5-chloro-2-benzothiazolinone) The substance was recrystallized from a mixture of petroleum ether and benzene and gives colorless flakes with a melting point of 86°C.

På tilsvarende måte som ovenfor kan folgende forbindelser fremstilles: 3-A-(2-lauroyloksyetyl)1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Maleatet utgjor farvelose krystaller med smp. 168 - 171°C. 3-/Tt—(2-linoloybksyetyl) -1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon som en olje. Maleatet utgjor farvelose krystaller med smp. 150 til 152°C (spalting). 3-A—(2-stearoyloksyetyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon i form av voksaktige krystaller med smp. 7<*>+ til 76°C. 3-/<t>t—(2-lauroyloksypropyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Maleatet har smp. 162 til 165 C. 3-/5—'(2-palmitoyloksypropyl)-1 -piperazinyl7karbonylmetyl-5-klor~2-benzotiazolinon i form av farvelost pulver med smp. 9*+ til 95°C. 3-ZI+-(2-linoloyloksypropyl) -1 -piperazinyl7iarbonylmetyl-5-klor-2-benzotiazolinon i form av en olje. Maleatet utgjor farvelose krystaller med smp. 1^7'til 1^9 C (spalting). 3-^+-(2-palmitoyloksyetyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzoksazolinon. Maleatet er et farvelost pulver med smp. 72 til 7<l>f°C. 3-metyl-6-klor-1 -Z1+-( 2-palmitoyloksyetyl)-1 -piperazinyUkarbonyl--metyl-2-benzimidazolinon med smp. 97 til 98°C. 3- £+~( 2.- f enylacetoksyetyl) -1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Hydrokloridet utgjor farvelose flak med smp. 206 til 207°C. 3-A-(2-f enylacetoksypropyl)-1 -piperaziny3_7karbonylmetyl-5-klor-2-benzotiazolinon. Hydrokloridet utgjor et farvelost pulver med smp. 250°C (spalting). 3-Z^- (2-0, k, 5, -trimetoksybenzoyloksy)etyl) -1 -piper azinyl7-karbonylmetyl-5-klor-2-benzotiazolinon. Maleatet har smp. 123 til 130°C (spalting). 3-/<*>+-(2-palmitoyloksyetyl)r1-piperazinyl7karbonylmetyl-5-trifluorometyl-2-benzotiazolinon. Farvelose krystaller med smp. 98 til 99°C. In a similar way as above, the following compounds can be prepared: 3-A-(2-lauroyloxyethyl)1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate forms colorless crystals with m.p. 168 - 171°C. 3-[Tt-(2-linoleoxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone as an oil. The maleate forms colorless crystals with m.p. 150 to 152°C (decomposition). 3-A-(2-stearoyloxyethyl)-1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone in the form of waxy crystals with m.p. 7<*>+ to 76°C. 3-(2-lauroyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 162 to 165 C. 3-[5-(2-palmitoyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone in the form of a colorless powder with m.p. 9*+ to 95°C. 3-ZI+-(2-linoloyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone in the form of an oil. The maleate forms colorless crystals with m.p. 1^7' to 1^9 C (cleavage). 3-^+-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone. The maleate is a colorless powder with m.p. 72 to 7<l>f°C. 3-methyl-6-chloro-1 -Z1+-(2-palmitoyloxyethyl)-1-piperazinylcarbonyl--methyl-2-benzimidazolinone with m.p. 97 to 98°C. 3- £+~( 2.- f enylacetoxyethyl) -1 -piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms colorless flakes with m.p. 206 to 207°C. 3-A-(2-phenylacetoxypropyl)-1-piperazinyl-3-7carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms a colorless powder with m.p. 250°C (decomposition). 3-Z^-(2-O,k,5,-trimethoxybenzoyloxy)ethyl)-1-piper azinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 123 to 130°C (decomposition). 3-[<*>+-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone. Colorless crystals with m.p. 98 to 99°C.

3-/I(—(2-steaiEyloksyetyl) -1 -piperazinyl7karbonylmetyl-5-trifluorometyl-2-benzotiazolinon. Farvelose krystaller av forbindelsen har smp. 95 til 96°C. 3-(1-(2-Steayloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone. Colorless crystals of the compound have a melting point of 95 to 96°C.

Eksempel Example

(1) Til en opplosning av 5-klor-2-okso-3-benzotiazolinylacetyl-klorid (1,3 g) °g kaliumkarbonat (1,3 g) i dimetylformamid (26 cc) tilsettes en opplosning av palmitoyloksyetylpiperazin (2,0 g) i dimetylformamid (5 cc). Blandingen omrores i 5 timer ved romtemperatur og etter avsluttet omsetning helles reaksjonsblandingen ut på isblandet vann og ekstraheres flere ganger med etylacetat. Etylacetatlaget vaskes med vann og torres så over vannfritt magnesiumsulfat. Losningsmidlet avdestilleres og således oppnådd rest oppleses i etylacetat og kromatograferes på aluminiumoksyd -under anvendelse av etylacetat og gir 3-^—(2-palmitoyloksyetyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzo-tiazolinon (0,7 g) som farvelose krystaller med smp. 8<*>+ til 86°C. (1) A solution of palmitoyloxyethylpiperazine (2.0 g) in dimethylformamide (5 cc). The mixture is stirred for 5 hours at room temperature and, after completion of the reaction, the reaction mixture is poured onto ice-mixed water and extracted several times with ethyl acetate. The ethyl acetate layer is washed with water and then dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue thus obtained is taken up in ethyl acetate and chromatographed on aluminum oxide using ethyl acetate to give 3-(2-palmitoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzo-thiazolinone (0.7 g) as colorless crystals with m.p. 8<*>+ to 86°C.

På tilsvarende måte kan folgende forbindelser fremstilles: 3-Æ-(2-lauroyloksyetyl) 1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Maleatet utgjor farvelose krystaller med smp. 168 til 171°C 3-Z?+-( 2-linoloyloksyetyl)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon i form av en olje. Maleatet utgjore farvelose krystaller med smp. 150 til 152°C (spalting). 3-/1*-- (2-stearoyloksyetyl) -T-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Voksaktige krystaller smelter ved 7k til 76°C. 3-Æ-(2-lauroyloksypropyl)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Maleatet har smp. 162 til 165°C. 3-/'+-(2-palmitoyloksypropyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Farvelost pulver med smp. 9<*>+ til 95°C. 2-linoloyloksypropyl)-1-piperazinyl.7karbonylmetyl-5-klor-2-benzotiazolinon i form; av en olje. Maleatet utgjore farvelose krystaller med smp. 15-7 til 15-9°C (spalting). 3-A— (2-palmitoyloksyetyl) -1 -piperazinyl7karbonylmetyl-5-klor-2-benzoksazolinon. Maleatet utgjore et farvelost pulver med smp. 72 til 7<l>+°C. In a similar way, the following compounds can be prepared: 3-Æ-(2-lauroyloxyethyl) 1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate forms colorless crystals with m.p. 168 to 171°C 3-Z?+-(2-Linoloyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone as an oil. The maleate forms colorless crystals with m.p. 150 to 152°C (decomposition). 3-(1*--(2-stearoyloxyethyl)-T-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. Waxy crystals melt at 7k to 76°C. 3-N-(2-lauroyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 162 to 165°C. 3-(2-palmitoyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. Colorless powder with m.p. 9<*>+ to 95°C. 2-linoloyloxypropyl)-1-piperazinyl.7carbonylmethyl-5-chloro-2-benzothiazolinone in form; of an oil. The maleate forms colorless crystals with m.p. 15-7 to 15-9°C (cleavage). 3-A-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone. The maleate forms a colorless powder with m.p. 72 to 7<l>+°C.

3-metyl-6-klor-1 - £+-{2-palmitoyloksyetyl) -1 -piperazinyl7karbonyl-metyl-2-benzimidazolinon med smp. 97 til 98 C. 3-methyl-6-chloro-1-£+-{2-palmitoyloxyethyl)-1-piperazinyl-7carbonyl-methyl-2-benzimidazolinone with m.p. 97 to 98 C.

3-/5--(2-fenylacetoksye tyl) -1 -piper azinyl7karbonylme tyl-5-klor-2-benzotiazolinon. Hydrokloridet utgjor farvelose flak med smp. 3-(5--(2-phenylacetoxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms colorless flakes with m.p.

206 til 207°C 206 to 207°C

3-/5—(2-f enylacetoksypropyl) -1 -piperazinyl7karbonylmetyl-5-klor-2- benzotiazolinon. Hydrokloridet er et farvelost pulver med smp. 250°C (spalting). 3-(5-(2-phenylacetoxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone). The hydrochloride is a colorless powder with m.p. 250°C (decomposition).

3- /5—( 2- Q ,5-, 5-trimetoksybenzoyloksy) etyl) -1 -piper aziny l/karbonyl - metyl-5-klor-2-benzotiazolinon. Maleatet har smp. 123 til 130°C (spalting). 3- /5-(2-Q,5-,5-trimethoxybenzoyloxy)ethyl)-1-piperazinyl/carbonyl-methyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 123 to 130°C (decomposition).

3-/5—( 2-palmitoyloksyetyl) -1 -piperazinyl7karbonylmetyl-5-trifluormetyl-2-benzotiazolinon. Farvelose krystaller herav har smp. 3-(5-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone). Colorless crystals thereof have m.p.

98 til 99°C 98 to 99°C

3-/5— (2-stearoyloksyetyl)-1-piperazinyl7karbonylmetyl-5-trifluormetyl-2-benzotiazolinon utgjores av farvelose krystaller med smp. 3-(5-(2-stearoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone) consists of colorless crystals with m.p.

95 til 96°C 95 to 96°C

Eksempel h Example h

(1) Til en opplosning av 5-klorbenzotiazolinon (0,93 g) i torr aceton (20 cc) tilsettes kaliumkarbonat (0,5 g) og 1-kloracetyl-5~(2-palmitoyloksyetyl)piperazin (2,1 g). Blandingen kokes under tilbakelop i 5■timer under omroring og reaksjons- (1) To a solution of 5-chlorobenzothiazolinone (0.93 g) in dry acetone (20 cc) is added potassium carbonate (0.5 g) and 1-chloroacetyl-5~(2-palmitoyloxyethyl)piperazine (2.1 g) . The mixture is refluxed for 5 hours with stirring and reaction

t t

blandingen filtreres og filtratet konsentreres. Til resten tilsettes vann og den vandige blanding ekstraheres med etylacetat. the mixture is filtered and the filtrate is concentrated. Water is added to the residue and the aqueous mixture is extracted with ethyl acetate.

Losningsmidlet avdestilleres og den derved oppnådde rest kromatograferes på aluminiumoksyd under anvendelse av etylacetat og gir 3-^-(2-palmitoyloksyetyl)-1-piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon (0,1 g) som farvelose krystaller med smp. 85- til 86°C. The solvent is distilled off and the resulting residue is chromatographed on alumina using ethyl acetate and gives 3-^-(2-palmitoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone (0.1 g) as colorless crystals with m.p. 85- to 86°C.

På tilsvarende måte kan folgende forbindelser fremstilles: 3-Z5--(2-lauroyloksyetyl)-1-piperazinyL7karbonylmetyl-5-klor-2-benzotiazolinon. Maleatet utgjor farvelose krystaller med smp. 168 til 171°C. 3-A-(2-linoloyloksyetyl) -1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon i form av en olje. Maleatet utgjor farvelose krystaller med smp. 150 til 152°C (spalting). 3_/<5>~(2-stearo<y>loks<y>et<y>l)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon i form av voksaktige krystaller med smp. 7h til 76°C. 3-Z5~(2-lauroyloksypropyl) -1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Maleatet har smp. 162 til 165°C. 3-Z5— (2-palmitoyloksypropyl)-1 -piperazinyl7karbonylmetyl-5-klor-2- benzotiazolinon i form av farvelost pulver med smp. 95- til 95°C. 3- /5—(2-linoloyloksypropyl)-1 -piperazinyl/karbonylmetyl-5-klor-2- benzotiazolinon i form av en olje. Maleatet utgjor farvelose krystaller med smp. 1^-7 til 1 5-9 C (spalting). 3- /5—(2-palmitoyloksyetyl)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzoksazolinon. Maleatet utgjor et farvelost pulver med smp. 72 til 7*f°C. In a similar way, the following compounds can be prepared: 3-Z5-(2-lauroyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate forms colorless crystals with m.p. 168 to 171°C. 3-A-(2-Linoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone in the form of an oil. The maleate forms colorless crystals with m.p. 150 to 152°C (decomposition). 3_/<5>~(2-stearo<y>lox<y>et<y>l)-1 -piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone in the form of waxy crystals with m.p. 7h to 76°C. 3-Z5-(2-lauroyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 162 to 165°C. 3-Z5-(2-palmitoyloxypropyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone in the form of colorless powder with m.p. 95 to 95°C. 3- /5-(2-linoloyloxypropyl)-1-piperazinyl/carbonylmethyl-5-chloro-2-benzothiazolinone in the form of an oil. The maleate forms colorless crystals with m.p. 1^-7 to 1 5-9 C (cleavage). 3- /5-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone. The maleate forms a colorless powder with m.p. 72 to 7*f°C.

3-metyl-6-klor-1-/5—( 2-palmitoyloksyetyl )-1 -piperazinyl7karto nyl-metyl-2-benzimidazolinon med smp. 97 til 98°C. 3-methyl-6-chloro-1-(5-(2-palmitoyloxyethyl)-1-piperazinyl-7-cartonyl-methyl-2-benzimidazolinone with m.p. 97 to 98°C.

3-/5-(2-fenylacetoksyetyl)-1 -piperazinyl7karbonylmetyl-5-klor-2-benzotiazolinon. Hydrokloridet utgjor farvelose flak med smp. 206 til 207°C. 3-(5-(2-Phenylacetoxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms colorless flakes with m.p. 206 to 207°C.

i in

3-/4-(2-fenylacetoksypropyl)-l-piperazinyl/karbonylmetyl-5-klor-2- benzotiazolinon. Hydrokloridet utgjor et farvelost pulver med smp. 250°C (spalting). 3-(4-(2-phenylacetoxypropyl)-1-piperazinyl/carbonylmethyl-5-chloro-2-benzothiazolinone). The hydrochloride forms a colorless powder with m.p. 250°C (decomposition).

3- /4-(2-(3,4,5-trimetoks<y>benzo<y>loksy)et<y>l-l-<p>i<p>erazin<y>l/karbonyl-metyl-5-klor-2-benzotiazolinon. Maleatet har smp. 123 til 130°C (spalting). 3- /4-(2-(3,4,5-trimethoxy<y>benzo<y>loxy)et<y>l-l-<p>i<p>erazin<y>l/carbonyl-methyl-5- chloro-2-benzothiazolinone The maleate has mp 123 to 130°C (decomposition).

3-/4- (2-palmitoyloksyetyl )-l-piperaziny],7karbonyImetyl-5-trifluormetyl-2-benzotiazolinon i form av farvelose krystaller med smp. 98 til 99°C. 3-(4-(2-palmitoyloxyethyl)-1-piperaziny],7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone in the form of colorless crystals with m.p. 98 to 99°C.

3-/4-(2-stearoyloksyetyl)-l-piperaziny l/karbonylmetyl-5-trifluor-metyl-2-benzbtiazolinon i form av farvelose krystaller med smp. 95 til 96°C. 3-(4-(2-stearoyloxyethyl)-l-piperaziny l/carbonylmethyl-5-trifluoromethyl-2-benzbthiazolinone in the form of colorless crystals with m.p. 95 to 96°C.

Claims (1)

Analogifremgangsmåte for fremstilling av nye, terapeutisk aktive acyloksyalkyl-heterocykliske forbindelser med den generelle formel (I)Analogous process for the preparation of new, therapeutically active acyloxyalkyl heterocyclic compounds of the general formula (I) hvori Z er svovel, oksygen eller lavere alkylimino, A er lavere alkylen, er hydrogen, halogen eller trifluormetyl, R2 er acyl valgt fra gruppen bestående av hoyere alifatisk acyl, fenyl(lavere)alkanoyl og benzoyl, hvori fenyldelen kan være substituert med opp til 3 halogenatomer, lavere alkylgrupper og/eller lavere alkoksygrupper, eller syreaddisjonssalter derav, karakterisert ved at a) en forbindelse med den generelle formel hvori Z og har den ovennevnte betydning, eller dens metallsalt, omsettes med en karbamoylforbindelse med den generelle formel hvori X er en syrerest og A og R2 har den ovennevnte betydning, eller b) en forbindelse med den generelle formel hvori Z og R^ har den ovennevnte betydning, eller dens reaktive derivat omsettes med et amin med den generelle formel hvori A og R2 har den ovennevnte betydning, eller et salt derav, eller c) en forbindelse med den generelle formel hvori Z og har den ovennevnte betydning, omsettes med en acyloksyalkylforbindelse med den generelle formel hvori X, A og R2 har den ovennevnte betydning, eller d) en forbindelse med den generelle formel hvori Z, A og R^ har den ovennevnte betydning, eller et salt derav, omsettes med et acylerende middel med den generelle formel hvori R2 har den ovennevnte betydning, eller dets reaktive derivat, hvoretter den resulterende forbindelse med formel I om onskes omdannes til sitt syreaddisjonssalt.wherein Z is sulfur, oxygen or lower alkylimino, A is lower alkylene, is hydrogen, halogen or trifluoromethyl, R2 is acyl selected from the group consisting of higher aliphatic acyl, phenyl(lower)alkanoyl and benzoyl, wherein the phenyl moiety may be substituted with up to 3 halogen atoms, lower alkyl groups and/or lower alkoxy groups, or acid addition salts thereof, characterized in that a) a compound with the general formula wherein Z and has the above meaning, or its metal salt, is reacted with a carbamoyl compound of the general formula in which X is an acid residue and A and R2 have the above meaning, or b) a compound of the general formula in which Z and R 2 have the above meaning, or its reactive derivative is reacted with an amine of the general formula in which A and R 2 have the above meaning, or a salt thereof, or c) a compound of the general formula in which Z and has the above-mentioned meaning, is reacted with an acyloxyalkyl compound of the general formula in which X, A and R 2 have the above-mentioned meaning, or d) a compound of the general formula in which Z, A and R 2 have the above-mentioned meaning, or a salt thereof, is reacted with an acylating agent of the general formula wherein R 2 has the above meaning, or its reactive derivative, after which the resulting compound of formula I is optionally converted to its acid addition salt.
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