DK160553B - Analogy process for preparing benzisothiazole- and benzisoxazolepiperazine derivatives - Google Patents

Description

iin

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Den foreliggende opfindelse vedrører en anal ogi fremgangsmåde til fremstilling af hidtil ukendte benzisothioazol- og benzisoxazolpipera-zin-derivater med anti-psykotisk eller neuroleptisk virkning.The present invention relates to an analogue and method for the preparation of novel benzisothioazole and benzisoxazole piperazine derivatives having anti-psychotic or neuroleptic activity.

Wu, USA-patentskrift nr. 3.398.151, Wu, et al., USA-patentskrift 5 nr. 3.717.634 samt tilsvarende Wu, et al. publikationer -- J. Med.Chem., 12, 876-881 (1969), 15, 477-479 (1972) -- beskriver på forskellig måde psykotrope azaspiro[4.5]decandion- og dialkylglutarimidforbindelser svarende til formel (1) 10 \Wu, U.S. Patent No. 3,398,151, Wu, et al., U.S. Patent No. 5,717,634, and correspondingly Wu, et al. Publications - J. Med.Chem., 12, 876-881 (1969), 15, 477-479 (1972) - variously describe psychotropic azaspiro [4.5] decandionic and dialkylglutarimide compounds corresponding to formula (1) 10

X N-erlkylen — N N-BX N-carbide - N N-B

/W w o 15 (1) 1 2 hvori R og R er al kyl eller forbundet til dannelse af -(CHg)^- eller -(CH2)5-, og B inter alia betegner phenyl plus forskellige heterocykliske grupper (alle med valgfrie substituenter): 20/ W wo 15 (1) 1 2 wherein R and R are all cooled or joined to form - (CH 2) 5 - or - (CH 2) 5-, and B inter alia represents phenyl plus various heterocyclic groups (all with optional substituents ): 20

-O -O O-O -O O

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Casten, et al., USA-patentskrift nr. 4.182.763 beskriver den anxiolytiske brug af forbindelse (2), der i den biologiske litteratur 30 omtales som buspiron.Casten, et al., U.S. Patent No. 4,182,763 discloses the anxiolytic use of compound (2), which in biological literature 30 is referred to as buspirone.

o // ___ -\ /-\ ' N-\ X N-(OIL).-N \—J \ /v / 24\_y\-^o // ___ - \ / - \ 'N- \ X N- (OIL) .- N \ —J \ / v / 24 \ _y \ - ^

35 Vv lN35 Vv lN

OISLAND

(2) 2(2) 2

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Buspiron er nært beslægtet med forbindelserne, som fremstilles ifølge opfindelsen, og har meget svag og kortvarig neuroleptisk aktivitet (se G.L. Sathananthan, MD, D.P.M., I. Sanghvi, PH.D., N. Phillips, MD og S. Gershon, MD. DPM., Therapeutic Research, vol. 18, side 5 701-705, (1975)).Buspirone is closely related to the compounds of the invention and has very weak and short-term neuroleptic activity (see GL Sathananthan, MD, DPM, I. Sanghvi, PH.D., N. Phillips, MD, and S. Gershon, MD. DPM., Therapeutic Research, Vol. 18, pages 5 701-705, (1975)).

Benica, et al., J. Am. Pharmaceutical Association, 451-456 (1950) 1 2 beskriver 3,3-dialkylglutarimider, hvori R er Cj_4 al kyl, og R er hydrogen eller alkyl som vist ved formel (3), og det anføres, at forbindelserne mangler signifikant fysiologisk aktivitet.Benica, et al., J. Am. Pharmaceutical Association, 451-456 (1950) 1 2 discloses 3,3-dialkylglutarimides wherein R is Cj_ al alkyl and R is hydrogen or alkyl as shown by formula (3) and it is stated that the compounds lack significant physiological activity.

10 ,o x> 15 R \\ o (3)10, o x> 15 R \ (o)

Thiazolidindioner er kendte. F.eks. henviser Jones et al., J. Chem.Thiazolidinediones are known. Eg. Jones et al., J. Chem.

20 Soc., London, 91-92 (1946) til 5,5-dialkyl-2,4-thiazolidindionbarbitur-syre-analoge, og det anføres, at en 5-spirocyclohexyl-2,4-thiazolidind-ion (4) fremkalder narkose og analgesia i mus.20 Soc., London, 91-92 (1946) to 5,5-dialkyl-2,4-thiazolidinedione barbituric acid analogs, and it is stated that a 5-spirocyclohexyl-2,4-thiazolidinedione (4) induces anesthesia and analgesia in mice.

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S .NHS .NH

IIII

30 0 (4)30 0 (4)

Forskellige typer 1,4-substituerede piperazin-derivater er også 35 i og for sig kendte som vist i de følgende referencer.Various types of 1,4-substituted piperazine derivatives are also known per se as shown in the following references.

GB-patentskrift nr. 2.023.594A omhandler l(R-alkyl)-4-(3-trifluor-methylthiophenyl)piperaziner, som er nyttige til behandling af nervøsitet og depression, med den almene formel (5) 3GB-A-2,023,594A discloses 1 (R-alkyl) -4- (3-trifluoro-methylthiophenyl) piperazines useful for the treatment of nervousness and depression, of the general formula (5) 3

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R-(CH2)n-1/^ ^ti 0-SCF3 5 (5) hvori n er 1-3, og R inter alia betegner heterocykliske grupper såsom 10 WiC/- Å~i 0 hvori m er 0 eller 1, og X er -S-, -0-, imino, alkyl-imino eller 15 methyl en.R- (CH2) n-1 / ^ to O-SCF3 5 (5) wherein n is 1-3 and R inter alia represents heterocyclic groups such as 10 WiC / - Å ~ in 0 wherein m is 0 or 1, and X is -S-, -O-, imino, alkyl-imino or methyl one.

Rojsner, et al., Collect. Czech. Chem. Commun., 40(4) 1218-1230 (1975) beskriver inter alia butyrophenon-derivater med formel (6) som led i et psykotropt struktur-aktivitet-relationsstudie.Rojsner, et al., Collect. Czech. Chem. Commun., 40 (4) 1218-1230 (1975) discloses inter alia butyrophenone derivatives of formula (6) as part of a psychotropic structure-activity relationship study.

20 ,__ n /-' ° / \ _ "Η j>-C-<cH2>3-^ 25 (6)20, __ n / - '° / \ _ "Η j> -C- <cH2> 3- ^ 25 (6)

Det kunne ikke på baggrund af de ovenfor nævnte referencer forventes, at de ifølge den foreliggende opfindelse tilvejebragte 1,2-benziso-thiazol eller 1,2-benzisoxazol-piperazin-derivater besidder kraftig 30 neuroleptisk eller anti-psykotisk aktivitet.On the basis of the references cited above, it was not expected that the 1,2-benzisothiazole or 1,2-benzisoxazole-piperazine derivatives provided by the present invention possess potent neuroleptic or antipsychotic activity.

Ved fremgangsmåden ifølge opfindelsen tilvejebringes der pipera-zinyl-derivater med neuroleptiske (anti-psykotiske) egenskaber, som er ejendommelige ved, at de har formel (I) 35 R-Γλ-ι- wl Jx/LzThe process of the invention provides piperazinyl derivatives having neuroleptic (anti-psychotic) properties which are characterized by having formula (I) 35 R-Γλ-ι-wl Jx / Lz

hvori R betegner gruppen Twherein R represents the group T

DK 160553β 4 F <C"2) 3' ’ F (CH2> 3- 5 (e) (f) hvori Y betegner oxygen eller svovl og Z, betegner hydrogen eller halogen, eller et farmaceutisk acceptabelt non-toxisk syreadditionssalt 10 deraf.Wherein Y represents oxygen or sulfur and Z, represents hydrogen or halogen, or a pharmaceutically acceptable non-toxic acid addition salt thereof.

Det skal forstås, at udtrykket halogen som her anvendt betyder fluor, iod, og fortrinsvis chlor og brom.It is to be understood that the term halogen as used herein means fluorine, iodine, and preferably chlorine and bromine.

De farmaceutisk acceptable syreadditionssalte ifølge opfindelsen er sådanne, hvori anionen ikke signifikant bidrager til saltets toxicitet 15 eller farmakologiske aktivitet, og som sådanne er de farmakologiske ækvivalenter til baserne med formel (I). De foretrækkes i almindelighed til medicinsk brug. I nogle tilfælde har de fysiske egenskaber, som gør dem mere ønskværdige til farmaceutisk formulering såsom opløselighed, mangel på hygroskopicitet, kompressibilitet med hensyn til tabletdannel-20 se og forenelighed med andre bestanddele, hvormed stoffet kan anvendes til farmaceutisk brug. Saltene fremstilles rutinemæssigt ved blanding af en base med formel (I) med den udvalgte syre, fortrinsvis ved kontakt i opløsning, under anvendelse af et overskud af almindeligt anvendte inerte opløsningsmidler såsom vand, ether, benzen, ethanol, ethylacetat, og 25 fortrinsvis acetonitril. De kan også fremstilles ved metathese eller behandling med en ionbytterharpiks under betingelser, hvor anionen af ét salt af en forbindelse med formel (I) erstattes af en anden anion under betingelser, som tillader adskillelse af de ønskede forbindelser, såsom ved fældning fra opløsning eller ekstraktion i et opløsningsmiddel eller 30 eluering fra eller tilbageholdelse på en ionbytterharpiks. Farmaceutisk acceptable syrer med henblik på saltdannelse af forbindelserne med formel (I) omfatter svovlsyre, phosphorsyre, saltsyre, hydrogenbromidsyre, hydrogeniodidsyre, citronsyre, eddikesyre, benzoesyre, kanelsyre, mandelsyre, phosphorsyre, salpetersyre, slimsyre, isethionsyre, palmi -35 tinsyre, heptansyre og andre.The pharmaceutically acceptable acid addition salts of the invention are those in which the anion does not significantly contribute to the toxicity or pharmacological activity of the salt and as such are the pharmacological equivalents to the bases of formula (I). They are generally preferred for medical use. In some cases, the physical properties which make them more desirable for pharmaceutical formulation such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation, and compatibility with other ingredients with which the substance can be used for pharmaceutical use, have. The salts are routinely prepared by mixing a base of formula (I) with the selected acid, preferably by contact in solution, using an excess of commonly used inert solvents such as water, ether, benzene, ethanol, ethyl acetate, and preferably acetonitrile. They can also be prepared by metathesis or treatment with an ion exchange resin under conditions where the anion of one salt of a compound of formula (I) is replaced by another anion under conditions which allow separation of the desired compounds, such as by precipitation from solution or extraction. in a solvent or elution from or retention on an ion exchange resin. Pharmaceutically acceptable acids for salt formation of the compounds of formula (I) include sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydrogen iodide acid, citric acid, acetic acid, benzoic acid, cinnamic acid, almond acid, phosphoric acid, nitric acid, mucic acid, isethionic acid, palmic acid and heptic acid. others.

Forbindelser med formel (I), hvori R er gruppen "e" eller "f", opnås ved en fremgangsmåde, som involverer alkylering af et piperazinyl-mellemprodukt med formel (III) 5Compounds of formula (I) wherein R is the group "e" or "f" are obtained by a process involving the alkylation of a piperazinyl intermediate of formula (III)

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HN \]—.- VJ { I 1 (III)HN \] —.- VJ {I 1 (III)

5 \γ/χΛ Z5 \ γ / χΛ Z

hvori Y er oxygen eller svovl, og Z er hydrogen eller halogen, med en forbindelse med formel (X) 10 - <o F\y^^ici,2h-x . <x> 15 hvori X har den ovenfor anførte betydning, og mest foretrukket chlor eller brom, i et for reaktionen inert opløsningsmiddel til tilvejebringelse af forbindelserne med formel (le) 20 /=\ :: ^ \_y 2 3 u] (Ie> 25 hvorefter (le) reduceres til dannelsen af de tilsvarende forbindelser med formel (If) /=\ OH y-ywherein Y is oxygen or sulfur and Z is hydrogen or halogen, with a compound of formula (X) 10 - <o F \ y ^^ ici, 2h-x. wherein X has the meaning given above, and most preferably chlorine or bromine, in a solvent inert for the reaction to provide the compounds of formula (Ie). 25 (d) is reduced to the formation of the corresponding compounds of formula (If) / = \ OH yy

Piperazinyl-benzisothiazol- og -benzisoxazol-mellemprodukter med formel (III) opnås ved omsætning af 3-chlor-6-Z-l,2-benzisothiazol eller 35 3-chlor-6-Z-l,2-benzisoxazol med overskud af piperazin ved forhøjet temperatur. F.eks. fremstilles udgangsmaterialet 3-chlor-l,2-benzisothiazol ved behandling af 1,2-benzisothiazol-3(2H)on med phosphorpentachlorid ved 100-140eC i 4 timer. En tilsvarende omdannelse af 1,2-benzisoxazol- 6Piperazinyl benzisothiazole and benzisoxazole intermediates of formula (III) are obtained by reaction of 3-chloro-6-Z-1,2-benzisothiazole or 3-chloro-6-Z-1,2-benzisoxazole with excess piperazine at elevated temperature. Eg. the starting material 3-chloro-1,2-benzisothiazole is prepared by treating 1,2-benzisothiazol-3 (2H) one with phosphorus pentachloride at 100-140 ° C for 4 hours. A corresponding conversion of 1,2-benzisoxazole-6

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3-on til 3-chlor-l,2-benzisoxazol udføres med phosphoroxychlorid/tri-ethylamin i henhold til proceduren ifølge H. Boshagen, Ber. 100, 3326 (1967).3-one to 3-chloro-1,2-benzisoxazole is carried out with phosphorus oxychloride / triethylamine according to the procedure of H. Boshagen, Ber. 100, 3326 (1967).

De her omhandlede forbindelser er værdifulde farmakologiske midler 5 med psykotrope egenskaber. I denne henseende udviser de selektiv centralnervesystemaktivitet ved non-toxiske doser, og de er af særlig interesse som neuroleptiske (anti-psykotiske) midler. Som for andre kendte anti-psykotika, fremkalder forbindelserne med formel (I) visse reaktioner i standard in vivo og in vitro farmakologiske testsystemer, som 10 vides at korrelere godt med angstfrigørelse og symptomer på akut og kronisk psykose hos mennesker. De følgende systemer er illustrative for sådanne konventionelle in vivo testsystemer, som anvendes til at klassificere og differentiere et psykotropt middel fra et non-specifikt CNS-depressivt middel og til at bestemme potentielle risici for bivirkninger 15 (f.eks. kataleptisk aktivitet). I relation til sidstnævnte er anti-psy-kotiske midler en gruppe, som vides at fremkalde sedation og ekstrapyri-midale reaktioner såsom akut torsions-dystoni, akathiasi, parkinsonisme, tardivdyskinæsi og autonome nervesystemeffekter.The compounds of this invention are valuable pharmacological agents 5 with psychotropic properties. In this regard, they exhibit selective central nervous system activity at non-toxic doses and are of particular interest as neuroleptic (anti-psychotic) agents. As with other known antipsychotics, the compounds of formula (I) induce certain reactions in standard in vivo and in vitro pharmacological test systems which are known to correlate well with anxiety release and symptoms of acute and chronic psychosis in humans. The following systems are illustrative of such conventional in vivo test systems used to classify and differentiate a psychotropic agent from a non-specific CNS depressant and to determine potential risks of adverse events (e.g., cataleptic activity). In relation to the latter, antipsychotic agents are a group known to induce sedation and extrapyramidal reactions such as acute torsional dystonia, akathiasia, parkinsonism, tardive dyskinesia and autonomic nervous system effects.

20 Opførselstest Reference20 Behavior Test Reference

Undertrykkelse af kondi- Albert, Pharmacologist, 4, 152(1962); tioneret undgåelsesreaktion Wu, et al., J. Hed. Chem., 12, (CAR) 876-881 (1969).Suppression of Condi- Albert, Pharmacologist, 4, 152 (1962); tional avoidance reaction Wu, et al., J. Hed. Chem., 12, (CAR) 876-881 (1969).

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Katalepsi Costal1, et al., Psychopharmacolo- gia, 34, 233-241 (1974); Berkson, J. Amer. Statist. Assoc., 48, 565-599 (1953).Catalepsy Costal1, et al., Psychopharmacology, 34, 233-241 (1974); Berkson, J. Amer. Statist. Assoc., 48, 565-599 (1953).

30 Kæmpende mus Tedeschi, et al., J. Pharmacol.Fighting mice Tedeschi, et al., J. Pharmacol.

Expt. Therap., 125, 28 (1959) "Rotarod" Kinnard, et al., J. Pharmacol. Expt.Expt. Therap., 125, 28 (1959) "Rotarod" Kinnard, et al., J. Pharmacol. Expt.

35 Therap., 121, 354 (1957).35 Therap., 121, 354 (1957).

Apomorphin-stereotypi Janssen, et al., Arzneimittel.Apomorphine stereotypy Janssen, et al., Drug.

Forsch., 17, 841 (1966).Research, 17, 841 (1966).

77

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Som yderligere indikation på psykotrop aktivitet og specificitet for de omhandlede forbindelser kan anvendes kendt in vitro centralnerve-systemreceptorbindings-metodologi. Visse forbindelser (der i almindelighed omtales som ligander) er blevet identificerede, som præferentielt 5 binder til specifikke højaffinitetspunkter i hjernevæv, som har at gøre med psykotrop aktivitet eller potentiel for bivirkninger. Inhibering af radiomærket ligandbinding til sådanne specifikke højaffinitetspunkter betragtes som et mål for en forbindelses evne til at indvirke på tilsvarende centralnervesystemfunktion eller til at bevirke bivirkninger in 10 vivo. Dette princip anvendes i de følgende eksempelvis angivne prøver.As further indication of psychotropic activity and specificity of the compounds of the invention, known in vitro central nervous system receptor binding methodology may be used. Certain compounds (commonly referred to as ligands) have been identified that preferentially bind to specific high-affinity points in brain tissue that have to do with psychotropic activity or potential for side effects. Inhibition of radiolabeled ligand binding to such specific high affinity points is considered a measure of a compound's ability to affect corresponding central nervous system function or to cause adverse effects in vivo. This principle is used in the following examples, for example.

Receptorbindinqsprøve ReferenceReceptor Binding Test Reference

Dopamin Burt, et al., Holec. Pharmacol., 15 12, 800 (1976); Science, 196, 326 (1977); Creese, et al.,Dopamine Burt, et al., Holec. Pharmacol., 12, 800 (1976); Science, 196, 326 (1977); Creese, et al.,

Science, 1921, 481 (1976).Science, 1921, 481 (1976).

Cholinergisk Yamamura, et al., Proc. Natn.Cholinergic Yamamura, et al., Proc. Natn.

20 Acad. Sci. USA 71 1725 (1974).20 Acad. Sci. U.S.A. 71, 1725 (1974).

a-receptor Crews, et al., Science 202: 322 (1978); Rosenblatt, et al.,α-receptor Crews, et al., Science 202: 322 (1978); Rosenblatt, et al.,

Brain Res. lf>0: 186 (1979); 25 U'Prichard, et al., Science 199: 197 (1978); U'Prichard, et al., Molec. Pharmacol. 13: 454 (1977) 30 Serotonin type 2 Peroutka og Snyder, Molec.Brain Res. lf> 0: 186 (1979); U'Prichard, et al., Science 199: 197 (1978); U'Prichard, et al., Molec. Pharmacol. 13: 454 (1977) Serotonin type 2 Peroutka and Snyder, Molec.

Pharmacol. 16: 687 (1979).Pharmacol. 16: 687 (1979).

Ifølge den ved de førnævnte tests etablerede farmakologiske profil har de omhandlede forbindelser med formel (I) lovende anti-psykotisk 35 potentiel, idet de er relativt kraftige i CAR-testen med orale ED5Q-vær-dier <100 mg/kg legemsvægt og IC^Q-værdier på <1000 nanomolar i ^H-spi-peron-dopamin receptorbindingsprøven. Aktivitet i CAR-testen og spipe-ronprøven betragtes som prædiktivt for antipsykotisk potentiel i menne- 8According to the pharmacological profile established by the aforementioned tests, the compounds of formula (I) have promising anti-psychotic potential, being relatively potent in the CAR test with oral ED5Q values <100 mg / kg body weight and IC Q values of <1000 nanomolar in the ^ H-spi-peron-dopamine receptor binding assay. Activity in the CAR test and the spipe ron test is considered predictive of antipsychotic potential in humans.

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sker. Med hensyn til selektiv anti-psykotisk aktivitet har foretrukne forbindelser blandt de omhandlede signifikant dopaminreceptorbindings-aktivitet, og de undertrykker CAR i rotter under kataleptiske doser.happens. With regard to selective antipsychotic activity, preferred compounds have significant dopamine receptor binding activity and they suppress CAR in rats during cataleptic doses.

Udtrykket systemisk administrering som her anvendt refererer til 5 orale, rektale og parenterale (dvs. intramuskulære, intravenøse og subkutane) veje. I almindelighed vil det vise sig, når en af de omhandlede forbindelser administreres oralt, hvilket er den foretrukne vej, at en større mængde af den aktive bestanddel kræves for at frembringe den samme virkning som en mindre mængde indgivet parenteralt. I overensstem-10 melse med god klinisk praksis foretrækkes det at administrere de omhandlede forbindelser på et koncentrationsniveau, der vil fremkalde effektive neuroleptiske (anti-psykotiske) virkninger uden at forårsage nogen skadelige eller uønskede bivirkninger.The term systemic administration as used herein refers to 5 oral, rectal and parenteral (i.e., intramuscular, intravenous and subcutaneous) routes. In general, when one of the subject compounds is administered, it will be found that the preferred route is that a greater amount of the active ingredient is required to produce the same effect as a smaller amount administered parenterally. In accordance with good clinical practice, it is preferred to administer the subject compounds at a concentration level that will produce effective neuroleptic (anti-psychotic) effects without causing any harmful or undesirable side effects.

Terapeutisk indgives de omhandlede forbindelser i almindelighed som 15 farmaceutiske præparater bestående af en effektiv anti-psykotisk mængde af en forbindelse med formel (I) eller et farmaceutisk acceptabelt syreadditionssalt deraf og en farmaceutisk acceptabel bærer. Farmaceutiske præparater, som giver fra ca. 1 til 500 mg af den aktive bestanddel pr. enhedsdosis, foretrækkes, og de fremstilles konventionelt som tabletter, 20 pastiller, kapsler, pulvere, vandige eller olieagtige suspensioner, siruper, eliksirer og vandige opløsninger.Therapeutically, the compounds of the invention are generally administered as 15 pharmaceutical compositions consisting of an effective antipsychotic amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions which provide from ca. 1 to 500 mg of the active ingredient per day. unit dose, are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions.

Foretrukne orale præparater er i form af tabletter eller kapsler, og de kan indeholde konventionelle excipienter, såsom bindemidler (f.eks. sirup, acacia, gelatine, sorbitol, tragacanth eller polyvinyl-25 pyrrolidon), fyldstoffer (f.eks. lactose, sukker, majsstivelse, calci-umphosphat, sorbitol eller glycin), smøremidler (f.eks. magnesiumstea-rat, talkum, polyethylenglycol eller siliciumdioxid), disintegrerings-midler (f.eks. stivelse) og befugtningsmidler (f.eks. natriumlaurylsulfat). Opløsninger eller suspensioner af en forbindelse med formel (I) 30 med konventionelle farmaceutiske vehikler anvendes til parenterale præparater, såsom en vandig opløsning til intravenøs injektion eller en olieagtig suspension til intramuskulær injektion. Sådanne præparater med den ønskede klarhed, stabilitet og egnethed til parenteral brug opnås ved at opløse fra 0,1 til 10 vægt% af den aktive bestanddel i vand eller 35 en vehikel bestående af en polyvalent alifatisk alkohol, såsom glycerin, propylenglycol og polyethylenglycoler eller blandinger deraf. Polyethy-lenglycolerne består af en blanding af ikke-flygtige, normalt flydende polyethylenglycoler, der er opløselige i både vand og organiske væsker,Preferred oral preparations are in the form of tablets or capsules and may contain conventional excipients such as binders (e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g., lactose, sugar , corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silica), disintegrating agents (e.g., starch), and wetting agents (e.g., sodium lauryl sulfate). Solutions or suspensions of a compound of formula (I) 30 with conventional pharmaceutical vehicles are used for parenteral preparations such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such preparations having the desired clarity, stability and suitability for parenteral use are obtained by dissolving from 0.1 to 10% by weight of the active ingredient in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propylene glycol and polyethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of non-volatile, normally liquid polyethylene glycols, which are soluble in both water and organic liquids.

9 DK 160553 B9 DK 160553 B

og som har molekylvægte fra ca. 200 til 1500.and having molecular weights from ca. 200 to 1500.

TABELTABLE

5 De nedenfor anførte forbindelser testedes for aktivitet i de tests der er beskrevet side 6 og 7. De nedenfor anførte data angår undertrykkelse af konditioneret undgåelsesreaktion (CAR) (test A) og katalepsi (test B) side 6 og dopamin receptorbindingsprøve (test C) på side 7. Alle doser er pr. gram, med mindre andet er angivet for in vivo assays.5 The compounds listed below were tested for activity in the tests described on pages 6 and 7. The data given below relate to suppression of conditioned avoidance reaction (CAR) (test A) and catalepsy (test B) page 6 and dopamine receptor binding test (test C) on page 7. All doses are per day. grams, unless otherwise indicated for in vivo assays.

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Forbindelse Eksempel _Forbindelsens navn_ E 1 4-[4-(l,2-benzisothiazol-3-yl)-l- piperazinyl-l-(4-fluorphenyl)-l- 15 butanon,hydrochlorid 6 2 a-[3-[4-(l,2-benzisothiazol-3-yl)-l- piperazinyl]propyl]-4-fluorbenzen-methanoljhydrochlorid 20 L 3 4-[4-(l,2-benzisoxazol-3-yl)-l- pi perazi nyl]-1-(4-f1uorphenyl) -1 -butanon,hydrochlorid, 25 M 4 a-[3-[4-(l,2-benzisoxazol-3-yl)-l- piperazinyl]propyl]-4-fluorbenzen-methanolCompound Example _ Name of Compound E E 4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-1- (4-fluorophenyl) -1-butanone hydrochloride 6 2 α- [3- [4 - (1,2-Benzisothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene-methanol hydrochloride L 3 4- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl ] -1- (4-fluorophenyl) -1-butanone hydrochloride, M 4 α- [3- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol

Forbinde!ser Test Resultater_ 30 E A ED50= 7,4mg/kg.Connect Test Results_ 30 E A ED 50 = 7.4mg / kg.

B ED50=16,4mg/kg.B ED 50 = 16.4 mg / kg.

C IC50=10,2nMC IC 50 = 10.2nM

G A ED50=2,4mg/kg.G A ED 50 = 2.4mg / kg.

B ED50=5,0mg/kg.B ED 50 = 5.0mg / kg.

C IC5Q=2,03nMC IC5Q = 2.03nM

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10 L A EDgQ=5,8mg/kg.10 L A EDgQ = 5.8mg / kg.

B ED50=39,9mg/kg.B ED 50 = 39.9mg / kg.

C IC50=73,4nMC IC 50 = 73.4 nm

5 Μ A ED50=lmg/kg.5 Μ A ED 50 = lmg / kg.

B ED50=2,2mg/kg.B ED 50 = 2.2mg / kg.

C IC50=29,5nMC IC 50 = 29.5nM

10 Opfindelsen belyses nærmere i de følgende eksempler.The invention is illustrated in more detail in the following examples.

Eksempel 1 4-r4-(l,2-Benzisothiazol-3-.y1)-l-piperazinyl1-l-(4-fluorphen.yl)-l- butanon 15Example 1 4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone

'-\>-wvrOrTO'- \> - wvrOrTO

20 (a) 2-(3-Chlorpropyl)-2-(4-fluorphenyl)-l,3-dioxan - Som anført i Chem. Abs. 63, 9959b (1965), tilbagesvales en blanding af 4-chlor-4,-fluorbutyrophenon (20 g), ethylenglycol (6,9 g) og p-toluensulfon- 25 syre (0,05 g) i 50 ml benzen i 30 timer, idet det dannede vand opsam les. Koncentration af reaktionsblandingen under vakuum giver 2-(3--chlorpropyl)-2-(4-fluorphenyl)-1,3-dioxan.(A) 2- (3-Chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane - As stated in Chem. Abs. 63, 9959b (1965), a mixture of 4-chloro-4, fluorobutyrophenone (20 g), ethylene glycol (6.9 g) and p-toluenesulfonic acid (0.05 g) is refluxed in 50 ml of benzene for 30 minutes. hours, with the resulting water being collected. Concentration of the reaction mixture under vacuum gives 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane.

(b) Titel produkt,hydrochlorid - En blanding af 2-(3-chlorpropyl)--2-(4-fIuorphenyl)-l,3-dioxan (4,31 g, 0,0176 mol), 3-(l-piperazinyl)- 30 1,2-benzisothiazol (3,86 g, 0,0176 mol), pulveriseret kaliumcarbonat (2,43 g, 0,0176 mol) og kaliumiodid (0,88 g, 0,0053 mol) i 180 ml tør acetonitril tilbagesvales i 20 timer. Reaktionsblandingen filtreres, koncentreres under vakuum, og resterende olie opløses i chloroform og filtreres. Koncentration af filtratet giver en olieagtig remanens, 35 som optages i 100 ml ethanol indeholdende 10 ml 3 N saltsyre, og der tilbagesvales i 15 minutter. Acetonitril sættes til den afkølede blanding, og det opnåede faste stof opsamles, 3,3 g, smp. 248-250°C. Krystallisation af dette materiale fra ethanol giver analytisk rent(b) Title product, hydrochloride - A mixture of 2- (3-chloropropyl) - 2- (4-fluorophenyl) -1,3-dioxane (4.31 g, 0.0176 mol), 3- (1- piperazinyl) - 1,2-benzisothiazole (3.86 g, 0.0176 mol), powdered potassium carbonate (2.43 g, 0.0176 mol) and potassium iodide (0.88 g, 0.0053 mol) in 180 ml dry acetonitrile is refluxed for 20 hours. The reaction mixture is filtered, concentrated in vacuo, and the residual oil is dissolved in chloroform and filtered. Concentration of the filtrate gives an oily residue which is taken up in 100 ml of ethanol containing 10 ml of 3 N hydrochloric acid and refluxed for 15 minutes. Acetonitrile is added to the cooled mixture and the resulting solid is collected, 3.3 g, m.p. 248-250 ° C. Crystallization of this material from ethanol gives analytically pure

DK 160553 BDK 160553 B

HH

4-[4-(l,2-benzisothiazol-3-yl)-l-piperazinyl]-l-(4-fluorphenyl)-l-butan-on,hydrochloric!, smp. 251-254eC.4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone, hydrochloricyl, m.p. 251-254eC.

Analyse beregnet for ^j^FNgOS'HCl: C, 60,06; H, 5,52; N, 10,01.Analysis calculated for m.p. FNgOS'HCl: C, 60.06; H, 5.52; N, 10.01.

5 Fundet: C, 59,70; H, 5,47; N, 9,78.Found: C, 59.70; H, 5.47; N, 9.78.

NMR (DMSO-dg): 2,12 (2H, m); 3,25 (6H, m); 3,56 (4H, m); 4,06 (2H, d, 12,0 Hz); 7,41 (4H, m); 8,08 (4H, m); 11,60 (IH, bs).NMR (DMSO-d 6): 2.12 (2H, m); 3.25 (6H, m); 3.56 (4H, m); 4.06 (2H, d, 12.0 Hz); 7.41 (4H, m); 8.08 (4H, m); 11.60 (1H, bs).

Eksempel 2 10 tt-[3-r4-(l,2-Benzisothiazol-3-y1)-l-piperaziny1lpropyn-4-f1uorbenzenmethanolExample 2 tt- [3- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] propyn-4-fluorobenzene methanol

/=\ OH ' y V/ = \ OH 'y V

15 f “·(εΗ2>3'\_/1— 20 Natriumborhydrid (1,0 g, 0,026 mol) sættes portionsvis til en omrørt suspension af 4-[4-(l,2-benzisothiazol-3-yl)-l-piperazinyl]-l-(4-fluorphenyl)-l-butanon,hydrochlorid (3,34 g, 0,008 mol) i 150 ml absolut ethanol. Blandingen omrøres i 20 timer, gøres sur med ethanol i sk hydro-genchlorid, omrøres i yderligere 2 timer og koncentreres under vakuum.Sodium borohydride (1.0 g, 0.026 mol) is added portionwise to a stirred suspension of 4- [4- (1,2-benzisothiazol-3-yl) -1 -piperazinyl] -1- (4-fluorophenyl) -1-butanone hydrochloride (3.34 g, 0.008 mol) in 150 ml of absolute ethanol. The mixture is stirred for 20 hours, acidified with ethanol in so-called hydrogen chloride, stirred for another 2 hours and concentrated under vacuum.

25 Resterende materiale deles mellem chloroform og 1 N vandig natriumhydroxid, og chloroformfasen tørres over magnesiumsulfat og koncentreres under vakuum til opnåelse af 2,31 g (69% udbytte) af titel forbindel sen i form af den frie base. Den frie base omdannes til hydrochloridet i ethanol med ethanolisk hydrogenchlorid til opnåelse af at-[3-[4-(l,2-benz-30 i sothiazol-3-yl)-1-piperazinyl]propyl]-4-fluorbenzenmethanol»hydrochlo-rid, smp. 200-202eC.The remaining material is partitioned between chloroform and 1N aqueous sodium hydroxide, and the chloroform phase is dried over magnesium sulfate and concentrated in vacuo to give 2.31 g (69% yield) of the title compound as the free base. The free base is converted to the hydrochloride in ethanol with ethanolic hydrogen chloride to give at- [3- [4- (1,2-benz-30 in sothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol »hydrochloride -rid, m.p. 200-202eC.

Analyse beregnet for C21H24FN30S*HC1: C, 59,78; H, 5,97; N, 9,96.Analysis calculated for C 21 H 24 FN 3 S * HCl: C, 59.78; H, 5.97; N, 9.96.

Fundet: C, 59,34; H, 5,95; N, 9,82.Found: C, 59.34; H, 5.95; N, 9.82.

35 NMR (DMSO-dg): 1,70 (4H, m); 3,40 (8H, m); 4,05 (2H, d, 12,0 Hz); 4,59 (IH, m); 5,30 (IH, bs); 7,35 (6H, m); 8,10 (2H, m); 11,20 (IH, bs).NMR (DMSO-d 6): 1.70 (4H, m); 3.40 (8H, m); 4.05 (2H, d, 12.0 Hz); 4.59 (1H, m); 5.30 (1H, bs); 7.35 (6H, m); 8.10 (2H, m); 11.20 (1H, bs).

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Eksempel 3 4-r4-(l,2-Benzisoxazol-3-yl )-l-piperazin.yn-l-(4-fluorphen,yl)-l-butanon 5 / \ 2 / \ Λ / \_/i Γ 10Example 3 4- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) yl-1-butanone 5β, 2β, β-β 10

Omsætning af 2-(3-chlorpropyl)-2-(4-fluorphenyl)-l,3-dioxan med 3-(l-piperazinyl)-l,2-benzisoxazol ved fremgangsmåden fra Eksempel 1 og omdannelse af den frie base til hydrochloridsaltet giver et 25% udbytte 15 af 4-[4-(1,2-benzisoxazol-3-yl)-l-piperazinyl]-l-(4-fluorphenyl)-l-butanon,hydrochlorid, smp. 260-262'C, fra methanol (25% udbytte).Reaction of 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane with 3- (1-piperazinyl) -1,2-benzisoxazole by the procedure of Example 1 and conversion of the free base to the hydrochloride salt gives a 25% yield of 4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone, hydrochloride, m.p. 260-262 ° C, from methanol (25% yield).

Analyse beregnet for C21**22^3*V^: C, 62,46; H, 5,75; N, 10,1.Calcd for C21 ** 223 * V +: C, 62.46; H, 5.75; N, 10.1.

Fundet: C, 62,18; H, 5,59; N, 10,50.Found: C, 62.18; H, 5.59; N, 10.50.

20 NMR (DMSO-dg): 2,11 (2H, m); 2,56 (2H, m); 3,40 (8H, m); 4,12 (2H, m); 7,33 (5H, m); 7,60 (IH, m): 8,06 (2H, m); 11,20 (IH, bs).NMR (DMSO-d 6): 2.11 (2H, m); 2.56 (2H, m); 3.40 (8H, m); 4.12 (2H, m); 7.33 (5H, m); 7.60 (1H, m): 8.06 (2H, m); 11.20 (1H, bs).

Eksempel 4 a- Γ3-Γ4-(1,2-Benzi soxazol-3-yl)-1-piperazi nylJpropyl1-4-Π uor-25 benzenmethanol F ( CH2i ]j- 30 ~Example 4 α- [3- [4- (1,2-Benzoxazol-3-yl) -1-piperazinyl] propyl] -4-fluoro-benzene methanol F (CH

Redukti on af 4-[4-(1,2-benzi soxazol-3-yl)-1-pi perazi nyl]-(4-f1uor-phenyl-l-butann,hydrochlorid (2,0 g, 0,005 mol) med natriumborhydrid 35 (0,57 g, 0,015 mol) i 200 ml absolut ethanol foretages i overensstemmelse med fremgangsmåden fra Eksempel 2. Resterende materiale efter koncentration af den surgjorte blanding gøres basisk med natriumhydroxid og ekstraheres med chloroform. De forenede ekstrakter tørres over magnesi-Reduction of 4- [4- (1,2-benzoxazol-3-yl) -1-piperazinyl] - (4-fluoro-phenyl-1-butane, hydrochloride (2.0 g, 0.005 mol) with Sodium borohydride 35 (0.57 g, 0.015 mole) in 200 ml of absolute ethanol is made according to the procedure of Example 2. Residual material after concentration of the acidified mixture is basified with sodium hydroxide and extracted with chloroform.

Claims (5)

5 Analyse beregnet for C21H24FN3°2‘ C, 68,28; H, 6,55; N, 11,38. Fundet: C, 68,13; H, 6,56; N, 11,43. NMR (CDCI3): 1,79 (4H, m); 2,60 (6H, m); 3,64 (4H, m); 4,68 (IH, m); 7,22 (8H, m). 10Analysis calculated for C 21 H 24 FN 3 ° 2 C, 68.28; H, 6.55; N, 11.38. Found: C, 68.13; H, 6.56; N, 11.43. NMR (CDCl 3): 1.79 (4H, m); 2.60 (6H, m); 3.64 (4H, m); 4.68 (1H, m); 7.22 (8H, m). 10 1. Anal ogi fremgangsmåde til fremstilling af benzisothioazol- eller benzisoxazolpiperazinderivater med formel (I), 15 /-\ R-N n—i- \ / H '-* N Y ^ Z 20 hvori R betegner gruppen "e" eller "f" /“V S /“\ ?H 25 \_/_c'(CH2)r F\_/CIMCVr (e) (f) hvori Y betegner oxygen eller svovl og Z, betegner hydrogen eller 30 halogen, KENDETEGNET ved, at man alkylerer et piperazinyl-mellemprodukt med formel (III) /~Y /s HH N-r;-“f η \ /* 35 v Y i (III) DK 160553 B hvori Y og Z har de ovenfor angivne betydninger, med en forbindelse med formel (X) 10 hvori X betegner syreresten af en reaktiv estergruppe, i et for reaktionen inert opløsningsmiddel til tilvejebringelse af forbindelserne med formel (le) 15 f 'Ø^^OiriCl <Ie) hvori Y og Z har de ovenfor angivne betydninger, hvorefter (le), om 20 ønsket, reduceres til dannelsen af de tilsvarende forbindelser med formel (If) hvori Y og Z har de ovenfor angivne betydninger, og/eller, om ønsket, 30 den resulterende forbindelse (I) omdannes til et farmaceutisk acceptabelt, non-toxisk syreadditionssalt deraf.An analogue and process for the preparation of benzisothioazole or benzisoxazole piperazine derivatives of formula (I), wherein R represents the group "e" or "f" / " VS / "\? H 25 \ _ / _ c '(CH2) r F \ _ / CIMCVr (e) (f) wherein Y represents oxygen or sulfur and Z, represents hydrogen or halogen, FEATURED by alkylating a piperazinyl intermediate of formula (III) / ~ Y / s HH No; - "f η \ / * 35 v Y in (III) DK 160553 B wherein Y and Z have the above meanings, with a compound of formula (X) 10 wherein X represents the acid residue of a reactive ester group, in a reaction inert solvent to provide the compounds of formula (Ie), wherein Y and Z have the meanings given above, wherein (Ie), if desired, is reduced to the formation of the corresponding compounds of formula (If) wherein Y and Z have the above meanings and / or, if desired, the resulting compound (I) is converted to a pharmaceutically acceptable, non-toxic acid addition salt thereof. 2. Fremgangsmåde ifølge krav 1, KENDETEGNET ved, at man ud fra tilsvarende udgangsmaterialer fremstiller 4-[4-(l,2-benziso-thiazol-3-yl)-l-piperazinyl]-l-(4-fluorphenyl)-l-butanon eller et far-35 maceutisk acceptabelt syreadditionssalt deraf.2. A process according to claim 1, characterized in that 4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1 is prepared from the corresponding starting materials. -butanone or a pharmaceutically acceptable acid addition salt thereof. 3. Fremgangsmåde ifølge krav 1, KENDETEGNET ved, at man ud fra tilsvarende udgangsmaterialer fremstiller 4-[-(l,2-benzisoxazol-3-yl)-l- DK 160553 B piperazinyl]-l-(4-fluorphenyl)-l-butanon eller et farmaceutisk acceptabelt syreadditionssalt deraf.3. A process according to claim 1, characterized in that 4 - [- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1 is prepared from corresponding starting materials. -butanone or a pharmaceutically acceptable acid addition salt thereof. 4. Fremgangsmåde ifølge krav 1, KENDETEGNET ved, at man ud fra 5 tilsvarende udgangsmaterialer fremstiller a-[3-[4-(l,2-benzisothiazol-3-yl)-l-piperazinyl]propyl]-4-fluorbenzenmethanol eller et farmaceutisk acceptabelt syreadditionssalt deraf.4. A process according to claim 1, characterized in that a- [3- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol or a pharmaceutically acceptable acid addition salt thereof. 5. Fremgangsmåde ifølge krav 1, KENDETEGNET ved, at man ud fra 10 tilsvarende udgangsmaterialer fremstiller a-[3-[4-(l,2-benzisoxazol-3-yl)-l-piperazinyl]propyl]-4-fluorbenzenmethanol eller et farmaceutisk acceptabelt syreadditionssalt deraf.5. A process according to claim 1, characterized in that a- [3- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol or a pharmaceutically acceptable acid addition salt thereof.