NO784039L - SUBSTITUTED 1,3-DIHYDROSPIRO (BENZO (C) THIOFENER) - Google Patents

SUBSTITUTED 1,3-DIHYDROSPIRO (BENZO (C) THIOFENER)

Info

Publication number
NO784039L
NO784039L NO784039A NO784039A NO784039L NO 784039 L NO784039 L NO 784039L NO 784039 A NO784039 A NO 784039A NO 784039 A NO784039 A NO 784039A NO 784039 L NO784039 L NO 784039L
Authority
NO
Norway
Prior art keywords
ether
compound
benzo
thiophene
piperidine
Prior art date
Application number
NO784039A
Other languages
Norwegian (no)
Inventor
Helen Hu Ong
Vernon Brian Anderson
James Arthur Profitt
Original Assignee
Hoechst Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of NO784039L publication Critical patent/NO784039L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Psychiatry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

Substituert 1,3-dihydrospiro-[benzo(c)thiofen]er og fremgangsmåter for deres fremstilling.^Substituted 1,3-dihydrospiro-[benzo(c)thiophene]s and methods for their preparation.^

Foreliggende oppfinnelse angår nye substituerte 1,3-dihydrospiro-[benzo(c)thiofen]er som kan brukes som midler mot depresjoner, og som beroligende midler, og videre angår oppfinnelsen mellomprodukter for de ovennevnte forbindelser, fremgangsmåter for deres fremstilling, samt fremgangsmåter for behandling med farmasøytisk effektive mengder av samme forbindelse foruten farmasøytiske preparater som inneholder slike forbindelser som de vesentlige aktive ingredienser. The present invention relates to new substituted 1,3-dihydrospiro-[benzo(c)thiophene]s which can be used as agents against depression and as sedatives, and further the invention relates to intermediates for the above-mentioned compounds, methods for their preparation, as well as methods for treatment with pharmaceutically effective amounts of the same compound in addition to pharmaceutical preparations containing such compounds as the essential active ingredients.

Så vidt vi vet er ikke forbindelser ifølge foreliggende oppfinnelse tidligere blitt beskrevet. Substituerte 1,3-dihydro-spiro-[isobenzofuran]er med følgende formel: To the best of our knowledge, compounds according to the present invention have not previously been described. Substituted 1,3-dihydro-spiro-[isobenzofuran]s with the following formula:

hvor R er hydrogen, alkyl, alkoksy-, trifluormetyl, halogen, hydroksy eller metylendioksy; R er hydrogen, alkyl, cykloalkylalkyl, alkenyl, fenylalkyl, difenylalkyl, difenylmetoksyalkyl, alkanoyl, fenylalkanoy1, benzoyl, benzoylalkyl, fenylhydroksyalky1, alkoksykarbony1, fenyloksykarboriy1 eller where R is hydrogen, alkyl, alkoxy, trifluoromethyl, halogen, hydroxy or methylenedioxy; R is hydrogen, alkyl, cycloalkylalkyl, alkenyl, phenylalkyl, diphenylalkyl, diphenylmethoxyalkyl, alkanoyl, phenylalkanoy1, benzoyl, benzoylalkyl, phenylhydroxyalkyl1, alkoxycarbonyl1, phenyloxycarboriy1 or

.cykloalkylkarbony1; R 2 er alkyl eller fenyl; Y er hydrogen, alkyl, alkoksy, hydroksy, m, n og n' er tall fra 1 til 3 så vel som deres optiske isomerer og farmasøytisk akseptable syre- .cycloalkylcarbonyl; R 2 is alkyl or phenyl; Y is hydrogen, alkyl, alkoxy, hydroxy, m, n and n' are numbers from 1 to 3 as well as their optical isomers and pharmaceutically acceptable acid-

addisjonssalter av ovennevnte forbindelser, er beskrevet av Victor J. Bauer et al. i US-patent nr. 3.959.475 utstedt addition salts of the above compounds are described by Victor J. Bauer et al. in US Patent No. 3,959,475 issued

25. mai 1976. På lignende måte beskriver Marxer et al. i "Spiro Piperidines I. Synthesis of Spiro[isobenzofuran-1(3H),4'-piperidines] and Spiro [ isobenzof uran-1 ( 3H)., 3 1 -piperidines ], " 25 May 1976. Similarly, Marxer et al. in "Spiro Piperidines I. Synthesis of Spiro[isobenzofuran-1(3H),4'-piperidines] and Spiro [isobenzofuran-1(3H).,3 1-piperidines],"

i J. Org. Chem. Vol. 40, nr. 10 (1975) forskjellige isobenzofuraner med følgende formel: in J. Org. Chem. Vol. 40, No. 10 (1975) various isobenzofurans with the following formula:

hvor X er hydrogen, halogen eller metoksy, R er metyl eller benzyl,' R' er fenyl, substituert fenyl, alkyl, fenylalkyl, difenylalkyl eller thienyl.ogR" er alkyl, fenyl, benzyl, 3-mety1-5-isoxazoly1 eller pyridyl. Det ble imidlertid i nevnte arbeid ikke beskrevet noen farmasøytisk.aktivitet for de be-skrevne isobenzofuranene. where X is hydrogen, halogen or methoxy, R is methyl or benzyl, R' is phenyl, substituted phenyl, alkyl, phenylalkyl, diphenylalkyl or thienyl, and R" is alkyl, phenyl, benzyl, 3-methyl-5-isoxazoly1 or pyridyl However, no pharmaceutical activity was described in said work for the isobenzofurans described.

Videre er det i ingen av de to ovennevnte arbeider an-tydet eller beskrevet de foreliggende forbindelser. Hver av nevnte arbeider beskriver isobenzofuraner og ikke benzothio-fener. Videre kan forbindelser ifølge foreliggende oppfinnelse ikke fremstilles ved de synteser som tidligere er beskrevet. Furthermore, the present compounds are not indicated or described in either of the two above-mentioned works. Each of the works mentioned describes isobenzofurans and not benzothiophenes. Furthermore, compounds according to the present invention cannot be prepared by the syntheses previously described.

Foreliggende oppfinnelse angår således nye substituerte 1,3-dihydrospiro-[benzo(c)thiofen]er med følgende formel: The present invention thus relates to new substituted 1,3-dihydrospiro-[benzo(c)thiophenes] with the following formula:

og deres optiske isomerer samt farmasøytisk akseptable salter av disse forbindelser, hvor R er hydrogen, hydroksy, benzoyloksy, laverealkyl, cykloalkyllaverealky1 eller cykloalkyllaverealkanoy1 hvor cykloalkyIdelen kan inneholde fra 3 til 6 karbonatomer, laverealkeny1, fenylalkyl, difenylalkyl, dife-nylmetoksyalky1, fenoksyalky1, laverealkanoy1, fenylalkanoyl, bezoyl, benzoylalkyl, fenylhydroksyalky1, alkyloksykarbonyl med fra 2 til 6 karbonatomer, fenyloksykarbony1, cykloalkylkarbonyl med 4 til 8 karbonatomer eller gruppen and their optical isomers as well as pharmaceutically acceptable salts of these compounds, where R is hydrogen, hydroxy, benzoyloxy, loweralkyl, cycloalkylloweralkyl1 or cycloalkylloweralkanoy1 where the cycloalkyl part may contain from 3 to 6 carbon atoms, loweralkeny1, phenylalkyl, diphenylalkyl, diphenylmethoxyalkyl1, phenoxyalkyl1, loweralkanoy1, phenylalkanoyl, bezoyl, benzoylalkyl, phenylhydroxyalkyl1, alkyloxycarbonyl having from 2 to 6 carbon atoms, phenyloxycarbonyl1, cycloalkylcarbonyl having 4 to 8 carbon atoms or the group

~^^2^m—^—R hvor Ph er fenyl; og hvor R og R kan være de samme eller forskjellige og hver kan være hydrogen, laverealkyl, laveréalkoksy, trifluormetyl, halogen, hydroksy, metylendioksy eller laverealkylthio; m, n og n' er tall fra 1 til 3; ~^^2^m—^—R where Ph is phenyl; and where R and R can be the same or different and each can be hydrogen, lower alkyl, lower alkyl, trifluoromethyl, halogen, hydroxy, methylenedioxy or lower alkylthio; m, n and n' are numbers from 1 to 3;

og hvor summen av n og n' er 3 eller 4. I ovennevnte beskri-velse betyr begrepet "lavere" grupper med opp til 6 karbonatomer. and where the sum of n and n' is 3 or 4. In the above description, the term "lower" means groups with up to 6 carbon atoms.

Syrer som kan brukes for fremstilling av farmasøytisk akseptable syreaddisjonssalter ifølge foreliggende oppfinnelse, innbefatter uorganiske syrer så som saltsyre, hydrobromsyre, svovelsyre, salpetersyre og perklorsyre, så vel som organiske syrer som tartarsyre, sitronsyre, eddiksyre, ravsyre, maleinsyre, fumarsyre og oksalsyre. Acids that can be used for the preparation of pharmaceutically acceptable acid addition salts according to the present invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic.

Visse forbindelser innenfor den. foreliggende, oppfinnelse har- større farmasøytisk aktivitet enn andre. De sist-nevnte forbindelser er ikke desto mindre ønskelige og brukbare som mellomprodukter for fremstilling av de mer aktive forbindelser. Foretrukne forbindelser er de hvor R er hydrogen, alkyl med fra 1 til 3 karbonatomer, spesielt metyl, eller substituert benzoylpropyl, og i de mest'foretrukne forbindelser er både n og n' begge 2. Certain connections within it. present invention has greater pharmaceutical activity than others. The last-mentioned compounds are nevertheless desirable and usable as intermediate products for the production of the more active compounds. Preferred compounds are those where R is hydrogen, alkyl of from 1 to 3 carbon atoms, especially methyl, or substituted benzoylpropyl, and in the most preferred compounds both n and n' are both 2.

Forbindelser ifølge foreliggende oppfinnelse kan fremstilles ved en av de mange fremgangsmåter som er beskrevet nedenfor. I disse beskrivelser har R, R 1 , R 2, n, n<1>og m den samme betydning som angitt ovenfor hvis intet annet er angitt. Compounds according to the present invention can be prepared by one of the many methods described below. In these descriptions, R, R 1 , R 2 , n, n<1> and m have the same meaning as stated above unless otherwise stated.

Fremgangsmåte AProcedure A

Et 2-bromfluorbenzen (1) hvor R<1>ikke er hydroksy, om-dannes .til sitt litiumderivat (II) på enhver hensiktsmessig måte, f.eks. ved en reaksjon med et laverealkyllitium med en temperatur mellom -100 og -50°C i et oppløsningsmiddel så som eter, heksan eller tetrahydrofuran. En foretrukken fremgangsmåte innbefatter reaksjon med butyllitium i tetrahydrofuran ved temperaturer mellom -70 og -60°C. A 2-bromofluorobenzene (1) where R<1> is not hydroxy is converted into its lithium derivative (II) in any suitable manner, e.g. by a reaction with a lower alkyllithium at a temperature between -100 and -50°C in a solvent such as ether, hexane or tetrahydrofuran. A preferred method involves reaction with butyllithium in tetrahydrofuran at temperatures between -70 and -60°C.

Det resulterende 2-litiumderivat omsettes med et cykloazalkanon med følgende formel: under de reaksjonsbetingelser som vanligvis brukes for denne type reaksjoner, f.eks. temperaturer fra -80 til -20, fortrinns-vis -80 til -40°C, i et oppløsningsmiddel så som eter, tetrahydrofuran eller heksan, hvorved man får et fenylcykloazalkanol The resulting 2-lithium derivative is reacted with a cycloazalkanone of the following formula: under the reaction conditions usually used for this type of reaction, e.g. temperatures from -80 to -20, preferably -80 to -40°C, in a solvent such as ether, tetrahydrofuran or hexane, whereby a phenylcycloazalkanol is obtained

Denne forbindelse behandles med et benzylmerkaptan med følgende formel: This compound is treated with a benzyl mercaptan of the following formula:

og en Lewis-syre så som titantetraklorid eller bortr.ifluorid- and a Lewis acid such as titanium tetrachloride or boron trifluoride

eterat ved temperaturer fra romtemperatur til 100°C, hvorved man får det tilsvarende benzylthiofenyIcykloazalkan (IV). etherate at temperatures from room temperature to 100°C, whereby the corresponding benzylthiophenylcycloazalkane (IV) is obtained.

Denne forbindelse cykliserés til det tilsvarende 1,3-dihydrospiro-[benzo(c)thiofen-cykloazalkan] (V), en forbindelse ifølge foreliggende oppfinnelse. - En foretrukken fremgangsmåte innbefatter bruken av natriumhydrid som et kondenserende/cykliserende middel med et oppløsningsmiddel så som dimetylformamid ved temperaturer fra 25 til 100°C. This compound is cyclized to the corresponding 1,3-dihydrospiro-[benzo(c)thiophene-cycloazalkane] (V), a compound according to the present invention. - A preferred method involves the use of sodium hydride as a condensing/cycling agent with a solvent such as dimethylformamide at temperatures from 25 to 100°C.

Fremgangsmåte BProcedure B

Et 1,3-dihydrospiro-[benzo(c)thiofen-cykloazalkan] (V) A 1,3-dihydrospiro-[benzo(c)thiophene-cycloazalkane] (V)

. fremstilt som beskrevet ovenfor, behandles med et klorformat, f.eks. et alkyl- eller fenylklorformat, ved temperaturer fra 15 til 125°C i et oppløsningsmiddel som toluen, benzen eller . prepared as described above, is treated with a chloroformate, e.g. an alkyl or phenyl chloroformate, at temperatures from 15 to 125°C in a solvent such as toluene, benzene or

metylenkior med eller uten et syreabsorberende middel så som natriumbikarbonat, hvorved man får fremstilt det tilsvarende N-alkoksykarbonyl- eller N-fenoksykarbonyl-1,3-dihydro-[benzo-(c)thiofen-cykloazalkan] (VI)/en forbindelse ifølge forelig- methylene chloride with or without an acid absorbing agent such as sodium bicarbonate, whereby the corresponding N-Alkoxycarbonyl- or N-phenoxycarbonyl-1,3-dihydro-[benzo-(c)thiophene-cycloazalkane] (VI)/a compound according to -

3 3

gende oppfinnelse, hvor R er laverealkyl eller fenyl. gending invention, where R is lower alkyl or phenyl.

Fremgangsmåte C Procedure C

En forbindelse ifølge foreliggende oppfinnelse fremstilt som beskrevet under fremgangsmåte B, behandles med.en base så som natrium eller kaliumhydroksyd i et oppløsnings-middel så som vann, etanol eller^etylenglykol.ved temperaturer fra 15°C til koketemperatur for reaksjonsblandingen, eller med en syre så som hydrogenbromid ieddiksyre ved temperaturer fra 15 til 125°C, hvorved man får tilveiebrakt det tilsvarende A compound according to the present invention prepared as described under method B is treated with a base such as sodium or potassium hydroxide in a solvent such as water, ethanol or ethylene glycol at temperatures from 15°C to the boiling temperature of the reaction mixture, or with a acid such as hydrogen bromide acetic acid at temperatures from 15 to 125°C, whereby the corresponding

. N-usubstituerte-1,3-dihydrospiro-[benzo(c)thiofen-cykloazalkan] . N-unsubstituted-1,3-dihydrospiro-[benzo(c)thiophene-cycloazalkane]

(VII), en forbindelse ifølge foreliggende oppfinnelse.(VII), a compound according to the present invention.

Fremgangsmåte D Procedure D

En forbindelse ifølge foreliggende oppfinnelse fremstilt under fremgangsmåte C kan behandles med en forbindelse med følgende formel: A compound according to the present invention produced under method C can be treated with a compound of the following formula:

hvor R 1er som definert tidligere, under normale reaksjonsbe-, tingelser, hvorved man får fremstilt en tilsvarende forbin--deise ifølge foreliggende oppfinnelse (VIII). En foretrukken fremgangsmåte innbefatter bruken av kaliumjodid som en star.tforbindelse for reaksjonen, natriumbikarbonat som syreabsorberende middel og dimetylformamid som et oppløsnings-middel ved en reaksjonstemperatur på ca. 75°C. Fremgangsmåte E Forbindelsen fremstilt som beskrevet under fremgangsmåte D underkastes en hydrolyse, hvorved man får den tilsvarende forbindelse ifølge foreliggende oppfinnelse where R 1 is as defined previously, under normal reaction conditions, whereby a corresponding compound according to the present invention (VIII) is produced. A preferred method involves the use of potassium iodide as a starting compound for the reaction, sodium bicarbonate as an acid absorbent and dimethylformamide as a solvent at a reaction temperature of approx. 75°C. Method E The compound prepared as described under method D is subjected to a hydrolysis, whereby the corresponding compound according to the present invention is obtained

som definert tidligere. En foretrukken fremgangsmåte innbefatter bruken av en sterk syre som 3N HC1 i et oppløsningsmiddel som vann eller etanol. as defined earlier. A preferred method involves the use of a strong acid such as 3N HCl in a solvent such as water or ethanol.

Fremgangsmåte FProcedure F

Et N-usubstituert-1,3-dihydrospiro-[benzo(c) thiofen-cykloazalkan ] (VII) fremstilt som beskrevet under fremgangsmåte C, kan på kjeht måte reageres med et alkanoylklorid eller syre- anhydrid, benzoylklorid eller anhydrid, aralkanoylklorid, alkylhalogenid, alkenylhalogenid, cykloalkanoylhalogenid eller aralkylhalogenid, hvorved man får fremstilt en tilsvarende forbindelse ifølge foreliggende oppfinnelse hvor R er alkanoyl, benzoyl, fenylalkanoyl, alkyl, alkenyl, cykloalkylkarbonyl, fenylalkyl eller cykloalkylalkyl. An N-unsubstituted-1,3-dihydrospiro-[benzo(c)thiophene-cycloazalkane] (VII) prepared as described under method C, can be conveniently reacted with an alkanoyl chloride or acid anhydride, benzoyl chloride or anhydride, aralkanoyl chloride, alkyl halide , alkenyl halide, cycloalkanoyl halide or aralkyl halide, whereby a corresponding compound according to the present invention is produced where R is alkanoyl, benzoyl, phenylalkanoyl, alkyl, alkenyl, cycloalkylcarbonyl, phenylalkyl or cycloalkylalkyl.

Fremgangsmåte GProcedure G

En forbindelse fremstilt som beskrevet ovenfor under fremgangsmåte B, E eller F hvor R er alkoksykarbony1, fenoksy-karbonyl, alkanoyl, benzoyl, fenylalkanoy1, cykloalkylkarbonyl eller benzoylalkyl kan reduseres på kjent måte med et reak-sjonsmiddel så som litiumaluminiumhydrid eller diboran til A compound prepared as described above under process B, E or F where R is alkoxycarbonyl, phenoxycarbonyl, alkanoyl, benzoyl, phenylalkanoy, cycloalkylcarbonyl or benzoylalkyl can be reduced in a known manner with a reagent such as lithium aluminum hydride or diborane to

den tilsvarende forbindelse ifølge foreliggende oppfinnelse, hvor R er alkyl, cykloalkyl,'fenylalkyl eller fenylhydroksyalkyl. the corresponding compound according to the present invention, where R is alkyl, cycloalkyl, phenylalkyl or phenylhydroxyalkyl.

Fremgangsmåte HProcedure H

En forbindelse ifølge foreliggende oppfinnelse fremstilt som beskrevet under fremgangsmåte C kan behandles med et peroksyd med følgende formel: hvor R er som definert tidligere,, under normale reaksjonsbetingelser hvorved man får den tilsvarende forbindelse ifølge foreliggende oppfinnelse. A compound according to the present invention prepared as described under method C can be treated with a peroxide of the following formula: where R is as defined previously, under normal reaction conditions whereby the corresponding compound according to the present invention is obtained.

En foretrukken .fremgangsmåte innbefatter bruken av natrium-karbonat, benzen og en temperatur på mellom 65 og 70°C. A preferred method involves the use of sodium carbonate, benzene and a temperature of between 65 and 70°C.

Fremgangsmåte IProcedure I

En forbindelse ifølge foreliggende oppfinnelse fremstilt som beskrevet under fremgangsmåte H kan behandles med en base så som NaOH under normale hydrolyserende betingelser, hvorved man får den tilsvarende forbindelse ifølge foreliggende oppfinnelse (X). A compound according to the present invention prepared as described under method H can be treated with a base such as NaOH under normal hydrolyzing conditions, thereby obtaining the corresponding compound according to the present invention (X).

Fremgangsmåte J Procedure J

En forbindelse ifølge foreliggende oppfinnelse fremstilt som beskrevet under fremgangsmåte A, B, C, E, F, G, H eller I som inneholder en alkoksygruppe eller en fenylring kan oppvarmes med en syre som som hydrobromsyre eller aluminium-tribromid, under normale betingelser for hydrolyserende reaksjoner, hvorved man får den tilsvarende hydroksy (fenoliske) forbindelse, dvs. en forbindelse ifølge foreliggende oppfinnelse. A compound according to the present invention prepared as described under process A, B, C, E, F, G, H or I containing an alkoxy group or a phenyl ring can be heated with an acid such as hydrobromic acid or aluminum tribromide, under normal conditions for hydrolyzing reactions, whereby the corresponding hydroxy (phenolic) compound is obtained, i.e. a compound according to the present invention.

Forbindelser ifølge foreliggende oppfinnelse kan brukes ved behandling av depresjoner hos pattedyr, noe som kan demon-streres ved deres evne til å hemme tetrabenazin-indusert depresjon hos mus (International Journal of Neuropharmacology, 8, 73 (1969)), en standardprøve for bedømmelse av antidepressive egenskaper.' Således vil en intraperitonal dose på 1,1 og 2,5 mg/kg kroppsvekt, henholdsvis av 1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin] og 1,3-dihydro-l<1->metyl-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin] gi en 50% hemning av ptosen i tetrabenazin-indusert depresjon hos mus. Disse data viser at forbindelser ifølge foreliggende oppfinnelse kan brukes som antidepressive midler hos pattedyr når de tilføres i mengder varierende fra 0,1. til 50 mg/kg kroppsvekt pr. døgn. Compounds of the present invention can be used in the treatment of depression in mammals, as demonstrated by their ability to inhibit tetrabenazine-induced depression in mice (International Journal of Neuropharmacology, 8, 73 (1969)), a standard test for the assessment of antidepressant properties.' Thus, an intraperitoneal dose of 1.1 and 2.5 mg/kg body weight, respectively, of 1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine] and 1,3 -dihydro-1<1->methyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine] produce a 50% inhibition of ptosis in tetrabenazine-induced depression in mice. These data show that compounds according to the present invention can be used as antidepressants in mammals when administered in amounts varying from 0.1. to 50 mg/kg body weight per day and night.

Videre kan forbindelser ifølge foreliggende oppfinnelse brukes som beroligende midler på grunn av deres depressive virk-ning på det sentrale nervesystem hos pattedyr. Denne evne kan vises i den såkalte Sidman Avoidance Paradigim (Science, 118, 157-8 (1953)), en standardprøve for beroligende midler, ifølge hvilken forbindelser ifølge foreliggende oppfinnelse viste seg brukbare som beroligende midler når de ble tilført mengder varierende fra 0,1 til 50 mg/kg kroppsvekt pr. døgn. Furthermore, compounds according to the present invention can be used as sedatives due to their depressant effect on the central nervous system in mammals. This ability can be demonstrated in the so-called Sidman Avoidance Paradigm (Science, 118, 157-8 (1953)), a standard test for tranquilizers, according to which compounds of the present invention proved useful as tranquilizers when administered in amounts varying from 0, 1 to 50 mg/kg body weight per day and night.

Andre forbindelser ifølge foreliggende oppfinnelse innbefatter: 1,3-dihydro-l<1->etoksykarbonyl-3-fenylspiro-[benzo-(c)thiofen-1,4'-piperidin], Other compounds according to the present invention include: 1,3-dihydro-1<1->ethoxycarbonyl-3-phenylspiro-[benzo-(c)thiophene-1,4'-piperidine],

1,3-dihydro-l'-[(3-hydroksy-3-fenyl)-propyl]-3-feny1-spiro-[benzo(c)thiofen-1,4'-piperidin], 1,3-dihydro-1'-[(3-hydroxy-3-phenyl)-propyl]-3-phenyl-1-spiro-[benzo(c)thiophene-1,4'-piperidine],

1'-[4-(4-fluorfenyl)-4-hydroksybuty1]-l,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin], 1'-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine],

1'-cykloheksylmetyl-1,3-dihydro-3-fenylspiro-[benzo-(c)thiofen-1,4<1->piperidin], 1'-cyclohexylmethyl-1,3-dihydro-3-phenylspiro-[benzo-(c)thiophene-1,4<1->piperidine],

1,3-dihydro-l'-di fenylmetoksyety1-3-fenylspiro-[benzo-(c)thiofen-1,4'-piperidin], 1,3-dihydro-1'-diphenylmethoxyethyl-1-3-phenylspiro-[benzo-(c)thiophene-1,4'-piperidine],

1<1->allyl-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin], 1<1->allyl-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine],

1,3-dihydro-l<1->metyl-3-(4-metoksyfenyl)-spiro-[benzo-(c)thiofen-1,4'-piperidin], 1,3-dihydro-1<1->methyl-3-(4-methoxyphenyl)-spiro-[benzo-(c)thiophene-1,4'-piperidine],

6-fluor-3-(4-fluorfenyl)-1,3-dihydro-l'-metylspiro-[benzo(c)thiofen-1,4'-piperidin], 6-fluoro-3-(4-fluorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c)thiophene-1,4'-piperidine],

1,3-dihydro-3-(4-metoksyfenyl)spiro-[benzo(c)thiofen-1,4'-piperidin], 1,3-dihydro-3-(4-methoxyphenyl)spiro-[benzo(c)thiophene-1,4'-piperidine],

1'-[3-(4-fluorbenzoyl)propyl]-l,3-dihydro-3-(4-metoksy-fenyl)spiro-[benzo(c)thiofen-1,4'-piperidin], 1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(4-methoxy-phenyl)spiro-[benzo(c)thiophene-1,4'-piperidine],

6-fluor-1'-[3-(4-fluorbenzoyl)propyl]-1,3-dihydro-3-fenylspiro[benzo(c)thiofen-1,4'-piperidin], 6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine],

4,6-difluor-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin], 4,6-difluoro-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine],

6-fluor-1'-[3-(4-fluorbenzoyl)propyl]-3-(4-fluorfenyl)-1,3-dihydro-spiro-[benzo(c)thiofén-1,4'-piperidin], 6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro-[benzo(c)thiophene-1,4'-piperidine],

1,3-dihydro-l'-(4,4-difenylbutyl)-3-(4-trifluormetyl-fenyl)-spiro-[benzo (c) thiofen-1, 4'-piperidin],. 3-(3-bromfenyl)-1,3-dihydro-l'-(3-fenoksypropy1)-spiro- 1,3-dihydro-1'-(4,4-diphenylbutyl)-3-(4-trifluoromethyl-phenyl)-spiro-[benzo (c)thiophene-1,4'-piperidine],. 3-(3-bromophenyl)-1,3-dihydro-1'-(3-phenoxypropyl)-spiro-

[benzo(c)thiofen-1,4'-piperidin], [benzo(c)thiophene-1,4'-piperidine],

1<1->benzoy1-1,3-dihydro-3-(4-hydroksyfenyl)spiro-[benzo(c)thiofen-1,4'-piperidin], 1<1->benzoyl-1,3-dihydro-3-(4-hydroxyphenyl)spiro-[benzo(c)thiophene-1,4'-piperidine],

1,3-dihydro-3-feny1-1'-fenylacetylspiro-[benzo(c) - thiofen-1,4'-piperidin], 1,3-dihydro-3-phenyl-1'-phenylacetylspiro-[benzo(c)-thiophene-1,4'-piperidine],

1,3-dihydro-3-(3,4-metylendioksyfenyl)-1'-metylspiro-[benzo(c)thiofen-1,4'-piperidin], 1,3-dihydro-3-(3,4-methylenedioxyphenyl)-1'-methylspiro-[benzo(c)thiophene-1,4'-piperidine],

1,3-dihydro-l'-hydroksy-3-(4-metoksyfenyl)spiro-. 1,3-dihydro-1'-hydroxy-3-(4-methoxyphenyl)spiro-.

[benzo(c)thiofen-1,4'-piperidin], [benzo(c)thiophene-1,4'-piperidine],

3- (3,4-diklorfenyl)-1,3-dihydro-l'-metylspiro-[benzo- " (c)thiofen-1,3'-pyrrolidin], 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-methylspiro-[benzo-(c)thiophene-1,3'-pyrrolidine],

1,3-dihydro-l'-mety1-3-(2-metylthiofenyl)spiro-[benzo(c)thiofen-1,4<1->piperidin], 1,3-dihydro-1'-methyl-3-(2-methylthiophenyl)spiro-[benzo(c)thiophene-1,4<1->piperidine],

1,3-dihydro-l<1->metyl-6-metylthio-3-fenylspiro-[benzo-(c)thiofen-1,3<1->pyrrolidin], 1,3-dihydro-1<1->methyl-6-methylthio-3-phenylspiro-[benzo-(c)thiophene-1,3<1->pyrrolidine],

1<1->cyklopropylacetyl-1,3-dihydro-3-fenylspiro-[benzo-(c)thiofen-1,4'-piperidin], 1<1->cyclopropylacetyl-1,3-dihydro-3-phenylspiro-[benzo-(c)thiophene-1,4'-piperidine],

6- metyl-l,3-dihydro-l'-mety1-3-fenylspiro-[benzo(c)-thiofen-1,4'-piperidin], 6-methyl-1,3-dihydro-1'-methyl-3-phenylspiro-[benzo(c)-thiophene-1,4'-piperidine],

7- metoksy-l,3-dihydro-l1-metyl-3-fenylspiro-[benzo-(c)thiofen-1,4<1->piperidin], 7- methoxy-1,3-dihydro-11-methyl-3-phenylspiro-[benzo-(c)thiophene-1,4<1->piperidine],

5-trifluormetyl-1,3-dihydro-l'-metyl-3-fenylspiro-[benzo(c)thiofen-1,41-piperidin] , 5-trifluoromethyl-1,3-dihydro-1'-methyl-3-phenylspiro-[benzo(c)thiophene-1,41-piperidine] ,

4- hydroksy-l,3-dihydro-l1-metyl-3-fenylspiro-[benzo-(c) thiof en-1 ,.4 '-piperidin ] , 4-hydroxy-1,3-dihydro-11-methyl-3-phenylspiro-[benzo-(c)thiophene-1,4'-piperidine],

5,6-metylendioksy-1,3-dihydro-l<1->metyl-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin], 5,6-methylenedioxy-1,3-dihydro-1<1->methyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine],

1,3-dihydro-l<1->metyl-3-(2-metoksyfenyl)spiro-[benzo-(c)thiofen-1,4'-piperidin], 1,3-dihydro-1<1->methyl-3-(2-methoxyphenyl)spiro-[benzo-(c)thiophene-1,4'-piperidine],

1'-benzoylpropyl-1,3-dihydro-3-fenylspiro-[benzo(c) - thiofen-1,4'-piperidin], 1'-benzoylpropyl-1,3-dihydro-3-phenylspiro-[benzo(c)-thiophene-1,4'-piperidine],

1<1->benzoylpropyl-1,3-dihydro-3-fenylspiro-[benzo(c)-thiofen-1,4<1->piperidin]-etylenketal, 1<1->benzoylpropyl-1,3-dihydro-3-phenylspiro-[benzo(c)-thiophene-1,4<1->piperidine]-ethylene ketal,

1'-(4-fluorfenetyl)-1,3-dihydro-3-fenylspiro-[benzo(c)-thiofen-1,4'-piperidin] og 1'-(4-fluorophenethyl)-1,3-dihydro-3-phenylspiro-[benzo(c)-thiophene-1,4'-piperidine] and

1,3-dihydro-l'-(3,4-dimetoksyfenyl)propyl-3-fenylspiro-tbenzo ( c) thiof en-1 , 4 1 -piperidin ] . 1,3-dihydro-1'-(3,4-dimethoxyphenyl)propyl-3-phenylspiro-tbenzo (c)thiophene-1,41-piperidine].

Effektive mengder av forbindelser ifølge oppfinnelsen kan tilføres en pasient på mange forskjellige måter, f.eks. oralt i form av kapsel eller tabletter, parenteralt i form av sterile oppløsninger eller suspensjoner og i visse tilfeller intravenøst i form av. sterile oppløsninger. De endelige pro-dukter i form av frie baser som er effektive i seg selv, kan opparbeides og tilføres i form av farmasøytisk akseptable syreaddisjonssalter for derved å gi bedre stabilitet, bedre utkrystallisering, øket oppløselighet og lignende. Effective amounts of compounds according to the invention can be administered to a patient in many different ways, e.g. orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions and in certain cases intravenously in the form of. sterile solutions. The final products in the form of free bases, which are effective in themselves, can be worked up and added in the form of pharmaceutically acceptable acid addition salts to thereby provide better stability, better crystallization, increased solubility and the like.

De aktive forbindelser ifølge oppfinnelsen kan til-føres oralt, f.eks. med et inert fortynningsmiddel eller med et inert bærestoff og de kan innkapsles i gelatin eller pres-ses sammen til tabletter. For orale terapeutiske behandlings-måter kan de aktive forbindelser ifølge foreliggende.oppfinnelse tilsettes fortynningsmidler og brukes i form av tabletter, kapsler, eleksirer, suspensjoner, siruper, tyggegummi og lignende. Slike preparater bør inneholde minst 0,5% av den aktive forbindelse, men dette kan variere alt etter hvilken form man ønsker, og variasjonen kan være fra 4. til 70 vekt-% . aktiv ingrediens pr. enhet. Den mengde aktive forbindelse man bruker i slike preparater bør være slik at man oppnår en egnet dosering. Foretrukne sammensetninger og preparater ifølge oppfinnelsen i form av en oral doseringsenhet bør inneholde fra 1,0 til 300 mg'aktiv forbindelse. The active compounds according to the invention can be administered orally, e.g. with an inert diluent or with an inert carrier and they can be encapsulated in gelatin or pressed together into tablets. For oral therapeutic treatment methods, the active compounds according to the present invention can be added to diluents and used in the form of tablets, capsules, elixirs, suspensions, syrups, chewing gum and the like. Such preparations should contain at least 0.5% of the active compound, but this can vary depending on which form is desired, and the variation can be from 4 to 70% by weight. active ingredient per unit. The amount of active compound used in such preparations should be such that a suitable dosage is achieved. Preferred compositions and preparations according to the invention in the form of an oral dosage unit should contain from 1.0 to 300 mg of active compound.

Tabletter, piller, kapsler og lignende kan også inne-holdes i følgende ingredienser: Et bindemiddel så som mikro-krystallinsk cellulose, gummi tragakant eller gelatin, samt fortynningsmidler som stivelse eller laktose, et nedbrytende middel så som algeninsyre, primogel, maisstivelse og lignende, et smøremiddel som magnesiumstearat eller Sterotex, et glide-middel så som kollodial silisiumdioksyd samt et søtningsmiddel så som sucrose eller saccarin og man kan tilsette smaksmidler så som peppermynte, metylsalicylat eller forskjellige fargestoffer. Når doseringsenheten er i form av en kapsel, så kan den i tillegg til det som er nevnt ovenfor inneholde et fly-tende fortynningsmiddel.så som en fettolje. Andre doserings-enheter kan inneholde andre forskjellige forbindelser som kan modifisere deres fysiske form, f.eks. forskjellige typer be-legg. Således kan tabletter eller piller belegges.med sukker, sjellakk eller andre midler. En sirup kan i tillegg til de. aktive forbindelser også inneholde succrose som et søtnings-middel og visse konserveringsmidler, fargestoffer etc. De forbindelser som brukes ved fremstillingen av de forskjellige preparater må være farmasøytisk rene og ikke-toksiske i de mengder som brukes. Tablets, pills, capsules and the like may also contain the following ingredients: A binder such as micro-crystalline cellulose, gum tragacanth or gelatin, as well as diluents such as starch or lactose, a disintegrating agent such as alginic acid, primogel, corn starch and the like, a lubricant such as magnesium stearate or Sterotex, a lubricant such as colloidal silicon dioxide and a sweetener such as sucrose or saccharin and you can add flavoring agents such as peppermint, methyl salicylate or various colourings. When the dosage unit is in the form of a capsule, it may, in addition to what is mentioned above, contain a liquid diluent such as a fatty oil. Other dosage units may contain other different compounds which may modify their physical form, e.g. different types of coatings. Thus, tablets or pills can be coated with sugar, sealing wax or other agents. A syrup can in addition to them. active compounds also contain sucrose as a sweetener and certain preservatives, dyes etc. The compounds used in the preparation of the various preparations must be pharmaceutically pure and non-toxic in the quantities used.

For parenteral tilførsel kan aktive forbindelser ifølge oppfinnelsen tilsettes en oppløsning eller suspensjon. Disse preparater bør også inneholde en farmasøytisk effektiv mengde, dvs. minst 0,1% aktiv forbindelse, men denne mengde kan variere fra 0,5 til 30 vekt-% av preparatet. Mengden av aktiv forbindelse i slike preparater bør være slik at man oppnår en egnet dose.' ForetrAkne sammensetninger og preparater ifølge oppfinnelsen•bør fremstilles slik at en parenteral dose-enhet inneholder mellom 0,5 og 100 mg aktiv forbindelse. For parenteral administration, active compounds according to the invention can be added to a solution or suspension. These preparations should also contain a pharmaceutically effective amount, i.e. at least 0.1% active compound, but this amount can vary from 0.5 to 30% by weight of the preparation. The amount of active compound in such preparations should be such that a suitable dose is obtained.' Preferred compositions and preparations according to the invention should be prepared so that a parenteral dose unit contains between 0.5 and 100 mg of active compound.

Oppløsninger eller suspensjoner kan også inneholde de følgende komponenter: Et sterilt fortynningsmiddel som vann for injeksjon, saltoppløsning, oljer, polyetylenglykoler, gly-serin, propylenglykol eller andre syntetiske oppløsningsmidler; antibakterielle midler som benzylalkohol eller metylparabener, antioksydasjonsmidler som ascorbinsyre eller liatriumbisulfitt, gelaterende midler som etylendiami.ntetraeddiksyre, buffere som acetater, sitrater eller fosfater samt midler for justering av tonisiteten som natriumklorid eller dekstrose. Det parenterale preparat kan innelukkes i ampuller, engangssprøyter eller fler-dosesprøyter fremstilt av glass eller plast. Solutions or suspensions may also contain the following components: A sterile diluent such as water for injection, saline, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens, antioxidants such as ascorbic acid or lithium bisulphite, gelling agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates as well as agents for adjusting the tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multi-dose syringes made of glass or plastic.

De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.

Eksempel 1Example 1

a. 46 ml 2,4 molar n-butyllitium ble i løpet av et kvar-ter tilsatt en blanding avkjølt til -70°C og bestående av 17,5 gram 2-bromfluorbenzen og 50 ml tetrahydrofuran. Etter total tilsetning ble blandingen rørt mellom -60 og -70°C i 15 min. slik at man fikk en fullstendig reaksjon, noe som resulterte i en svakt brun oppløsning. En blanding av 11,3 g l-metyl-4-piperidon i' 20 ml tetrahydrofuran ble tilsatt oppløsningen slik. at man holdt temperaturen-under -60°C. Deretter ble blandingen rørt ved samme lave temperatur i 1 time før den langsomt ble oppvarmet til romtemperatur. Vann ble tilsatt og man fikk en bifaseblanding, dvs. en organisk og en vandig fase. Den orga- a. 46 ml of 2.4 molar n-butyllithium was added over a quarter of an hour to a mixture cooled to -70°C and consisting of 17.5 grams of 2-bromofluorobenzene and 50 ml of tetrahydrofuran. After total addition, the mixture was stirred between -60 and -70°C for 15 min. so that a complete reaction was obtained, which resulted in a slightly brown solution. A mixture of 11.3 g of 1-methyl-4-piperidone in 20 ml of tetrahydrofuran was added to the solution as follows. that the temperature was kept below -60°C. The mixture was then stirred at the same low temperature for 1 hour before it was slowly warmed to room temperature. Water was added and a biphasic mixture was obtained, i.e. an organic and an aqueous phase. The orga-

niske fasen ble oppsamlet mens den vandige fasen ble ekstra-The liquid phase was collected while the aqueous phase was extracted

hert tre ganger med eter, og eterekstraktene ble slått sammen med nevnte organiske fase. Den samlede organiske oppløsningen ble så ekstrahert, med et overskudd av 2N saltsyre og kastet. Syreoppløsningen ble gjort basisk med ammoniumhydroksyd, noe hardened three times with ether, and the ether extracts were combined with said organic phase. The combined organic solution was then extracted with an excess of 2N hydrochloric acid and discarded. The acid solution was made basic with ammonium hydroxide, slightly

som ga en tung olje som løste seg i en 1:1 etylacetat-eterblanding. Denne oppløsning ble tørket og så konsentrert til tørrhet, hvorved man fikk en viskøs olje som utkrystalliserte seg ved avkjøling. Det faste produktet ble omkrystallisert fra en benzen-heksanblanding, hvorved man fikk prismer,-smeltepunkt 120-129°C av 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperidin. which gave a heavy oil which dissolved in a 1:1 ethyl acetate-ether mixture. This solution was dried and then concentrated to dryness, whereby a viscous oil was obtained which crystallized on cooling. The solid product was recrystallized from a benzene-hexane mixture, whereby prisms were obtained, melting point 120-129°C of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.

b. En reaksjonsblanding av 4,5 g av 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperidin, 8 ml benzylmerkaptan, 10 ml bortrifluorideterat og 10 ml iseddik ble rørt ved 65°C i 16 timer. Overskuddet av reagensene ble fjernet ved 70°C i vakuum, og. residumet ble oppløst i en 1:1 blanding av eter og 2N saltsyre og så hensatt ved en lav temperatur i 2 timer. Den avkjølte blandingen ble filtrert og man oppsamlet det krystallinske produktet. Dette ble omkrystallisert fra aceton-eter og man b. A reaction mixture of 4.5 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine, 8 ml of benzyl mercaptan, 10 ml of boron trifluoride etherate and 10 ml of glacial acetic acid was stirred at 65°C for 16 hours. The excess of the reagents was removed at 70°C in vacuum, and. the residue was dissolved in a 1:1 mixture of ether and 2N hydrochloric acid and then left at a low temperature for 2 hours. The cooled mixture was filtered and the crystalline product collected. This was recrystallized from acetone-ether and methanol

fikke fargeløse prismer, smeltepunkt 182-184°C av 4-benzylthio-4-(2-fluorfenyl)-1-metylpiperidinhydroklorid. c. En blanding av 0,9 g 50% natriumhydrid i 20 ml dimetylsulfoksyd ble oppvarmet til 85°C under en nitrogenatmos-fære i 30 min., hvorved man fikk en oppløsning av natrium-metyl-sulfinyl.metid. Denne oppløsning ble avkjølt til romtemperatur. Deretter tilsatte man en oppløsning av . 4,9 g 4-benzylthio-4-(2-fluorfenyl)-1-metylpiperidin fri base, i 10 ml dimetylsulfoksyd i løpet av 5 minutter. Blandingen ble så rørt ved romtemperatur i 1 time og så helt over' i isvann. Det resulterende faste stoff ble oppsamlet ved filtrering, omkrystallisert fra en eter-heksanblanding, hvorved man fikk fargeløse prismer, smeltepunkt 120-121°C, av 1,3-dihydro-l'-metyl-3-fenylspiro-[ benzo, (c) thiofen-1,4'-pipe ri din]. gave colorless prisms, mp 182-184°C of 4-benzylthio-4-(2-fluorophenyl)-1-methylpiperidine hydrochloride. c. A mixture of 0.9 g of 50% sodium hydride in 20 ml of dimethylsulfoxide was heated to 85°C under a nitrogen atmosphere for 30 min., whereby a solution of sodium methylsulfinylmethide was obtained. This solution was cooled to room temperature. A solution of . 4.9 g of 4-benzylthio-4-(2-fluorophenyl)-1-methylpiperidine free base, in 10 ml of dimethyl sulfoxide over 5 minutes. The mixture was then stirred at room temperature for 1 hour and then completely poured into ice water. The resulting solid was collected by filtration, recrystallized from an ether-hexane mixture to give colorless prisms, mp 120-121°C, of 1,3-dihydro-1'-methyl-3-phenylspiro-[benzo, (c ) thiophene-1,4'-pipe ri din].

Analyse: Beregnet for CigH21NS: 77,24%C, 7,17%H, 4,74%N, 10,85%S. Analysis: Calculated for CigH21NS: 77.24%C, 7.17%H, 4.74%N, 10.85%S.

Funnet: 77,31%C, 7,20%H, 4,59%N, 10,71%S. d. Ved å bruke l-metyl-3-pyrrolidon isteden for 1-metyl-4-piperidon i fremgangsmåte A, kan man få fremstilt 3-(2-fluorfenyl)-3-hydroksy-l-metylpyrrolidin. Found: 77.31%C, 7.20%H, 4.59%N, 10.71%S. d. By using 1-methyl-3-pyrrolidone instead of 1-methyl-4-piperidone in method A, 3-(2-fluorophenyl)-3-hydroxy-1-methylpyrrolidine can be produced.

v ■ v ■

e. Ved å gå ut fra 3-(2-fluorfenyl(-3-hydroksy-l-metylpyrrolidin og bruke fremgangsmåten A, kan man få fremstilt 1,3-dihydro-l1-metyl-3-fenylspiro-[benzo(c)thiofen-1,3' - pyrrolidin]. e. By starting from 3-(2-fluorophenyl(-3-hydroxy-l-methylpyrrolidine) and using method A, 1,3-dihydro-l1-methyl-3-phenylspiro-[benzo(c) thiophene-1,3'-pyrrolidine].

f. Ved å bruke 1-benzy1-3-pyrrolidon i stedet for l-metyl-3-pyrrolidon i fremgangsmåten fra eksempel ld, kan man få fremstilt 1'-benzyl-1,3-dihydro-3-fenylspiro-[benzo(c)-thiofen-1,3'-pyrrododin]. f. By using 1-benzyl-3-pyrrolidone instead of 1-methyl-3-pyrrolidone in the method from example 1d, 1'-benzyl-1,3-dihydro-3-phenylspiro-[benzo( c)-thiophene-1,3'-pyrrhodine].

g. Ved å bruké l-metyl-3-piperidon i stedet for 1-mety 1-4-piperido.n i fremgangsmåten fra eksempel la, så kan man få fremstilt 3-(2-fluorfenyl)-3-hydroksy-l-metylpiperidin. g. By using 1-methyl-3-piperidone instead of 1-methyl-1-4-piperidone in the method from example la, 3-(2-fluorophenyl)-3-hydroxy-1-methylpiperidine can be produced .

h. Hvis man går ut fra 3-(2-fluorfeny1)-3-hydroksy-. 1-mety lpiperidin, i fremgangsmåten fra eksempel lb og lc, s.å kan man få fremstilt 1,3-dihydro-l'-metyl-3-fenylspiro-[benzo-(c)thiofen-1,31-piperidin] . h. If one starts from 3-(2-fluorophenyl)-3-hydroxy-. 1-Methylpiperidine, in the process from examples 1b and 1c, 1,3-dihydro-1'-methyl-3-phenylspiro-[benzo-(c)thiophene-1,31-piperidine] can then be produced.

Eksempel 2Example 2

a. 9,9 ml (11,9 g) 4-klorbenzylmerkaptan og 11,1 ml bortrifluorideterat ble tilsatt 5,0 g 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperidin fra eksempel la, i 11,1 ml iseddik. Reaksjonsblandingen ble rørt ved 55-60°C i 48 timer. Overskuddet av reagenset ble fjernet ved 80°C i vakuum, og residumet ble oppløst i en 1:1 eter-2N samtsyreblanding. Man fikk en bifaseblanding som ble rørt i 2\ time og så i ytterligere 10 minutter etter at 50 ml is var tilsatt. Eterlaget ble så a. 9.9 ml (11.9 g) of 4-chlorobenzyl mercaptan and 11.1 ml of boron trifluoride etherate were added to 5.0 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine from Example 1a, in 11.1 ml glacial acetic acid. The reaction mixture was stirred at 55-60°C for 48 hours. The excess of the reagent was removed at 80°C in vacuo, and the residue was dissolved in a 1:1 ether-2N acetic acid mixture. A biphasic mixture was obtained which was stirred for 2.5 hours and then for a further 10 minutes after 50 ml of ice had been added. The ether layer became so

helt av. Det. vandige lag ble deretter vasket først med eter og så filtrert for oppsamling av et råprodukt. Dette ble vasket med en liten mengde vann og så en større mengde eter hvorved man fikk et hvitt pulver. Dette pulveret ble omkrystallisért fra aceton, hvorved man fikk hvite krystaller, smeltepunkt 164-166<Q>C av 4-(4-klorbenzylthio)-4-(2-fluorfenyl)-1-metyl-piperidinhydroklorid. completely off. The. aqueous layers were then washed first with ether and then filtered to collect a crude product. This was washed with a small amount of water and then a larger amount of ether to give a white powder. This powder was recrystallized from acetone to give white crystals, mp 164-166<Q>C of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methyl-piperidine hydrochloride.

Analyse:Analysis:

Beregnet for<C>i<g>H21NClFS•HC1: 59,08%C, 5,74%H, 3,63%N, 4,92%F Funnet: 59,04%C, 5,56%H, 3,68%N, 4,78%F Calculated for<C>i<g>H21NClFS•HC1: 59.08%C, 5.74%H, 3.63%N, 4.92%F Found: 59.04%C, 5.56%H, 3.68%N, 4.78%F

b. En oppløsning av natrium-metylsulfinylmetid ble fremstilt av 0,7 g 50% natriumhydrid og 15 ml dimetylsulfoksyd som i eksempel lc- En oppløsning av 4,2 g av 4-(4-klorbenzy1-thio)-4-(2-fluorfeny1)-1-metylpiperidin fri base av a,•i 15 ml dimetylsulfoksyd ble tilsatt denne oppløsning i løpet av 3 min. b. A solution of sodium methylsulfinyl methide was prepared from 0.7 g of 50% sodium hydride and 15 ml of dimethyl sulfoxide as in example 1c- A solution of 4.2 g of 4-(4-chlorobenzyl-thio)-4-(2- fluorophenyl)-1-methylpiperidine free base of a,•in 15 ml of dimethylsulfoxide was added to this solution over the course of 3 minutes.

Blandingen ble deretter rørt ved romtemperatur i 1 time og så helt over i 70 ml isvann. Blandingen ble fortynnet med vann til 120 ml totalt før filtrering for oppsamling av råproduktet. Produktet ble vasket med vann og så oppløst i eter. Eter-oppløsningen ble deretter vasket tre ganger med vann og en gang med en mettet natriumkloridoppløsning og deretter tørket, noe som ga gulhvite krystaller. Disse ble kromatografert med eter gjennom en aluminiumoksydkolonne og dette ga hvite krystaller, smp. 121-123°C av 3-(4-klorfenyl)-1,3-dihydro-l'-metylspiro-[benzo(c)thiofen-1,41-piperidin]. The mixture was then stirred at room temperature for 1 hour and then poured into 70 ml of ice water. The mixture was diluted with water to a total of 120 mL before filtration to collect the crude product. The product was washed with water and then dissolved in ether. The ether solution was then washed three times with water and once with a saturated sodium chloride solution and then dried to give yellowish white crystals. These were chromatographed with ether through an alumina column and this gave white crystals, m.p. 121-123°C of 3-(4-chlorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c)thiophene-1,41-piperidine].

Analyse:Analysis:

Beregnet for C19H20C1NS: 69,19%C, 6,11%H, 4,25%N, 10,75%C1. Calculated for C19H20C1NS: 69.19%C, 6.11%H, 4.25%N, 10.75%C1.

Funnet: 69,24%C, 6,21%H, 3,96%N, 10,74%C1. Found: 69.24%C, 6.21%H, 3.96%N, 10.74%C1.

Eksempel 3Example 3

En blanding av. 2,3 g 1,3-dihydro-l<1->metyl-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin] eksempel 1, 1,4 g fenylklorformat og 0,5 g natriumbikarbonat i 40 ml metylenklorid ble rørt ved romtemperatur i 4 timer og deretter filtrert. Filtratet ble så vasket med en fortynnet natriumhydroksydoppløsning. og vann og så tørket. Oppløsningsmidlet ble fjernet i vakuum, noe som ga et fast residum som ble omkrystallisert fra en benzen-heksanblanding, noe som ga rosetter, smp. 171-173°C av 1,3-dihydro-l'-fenoksykarbony1-3-fenylspiro-[benzo(c)thiofen-1,4' -piperidin]. A mixture of. 2.3 g of 1,3-dihydro-1<1->methyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine] Example 1, 1.4 g of phenylchloroformate and 0.5 g of sodium bicarbonate in 40 ml of methylene chloride was stirred at room temperature for 4 hours and then filtered. The filtrate was then washed with a dilute sodium hydroxide solution. and water and then dried. The solvent was removed in vacuo to give a solid residue which was recrystallized from a benzene-hexane mixture to give rosettes, m.p. 171-173°C of 1,3-dihydro-1'-phenoxycarbonyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine].

Beregnet for C25H23<N>02S:74,78%C, 5,77% H, 3,49%N.Calculated for C25H23<N>02S: 74.78%C, 5.77% H, 3.49%N.

Funnet: 75,04%C,'5,48%H, 3,43%N. Found: 75.04%C,'5.48%H, 3.43%N.

Eksempel 4Example 4

a. En blanding av 3,0 g 1,3-dihydro-l1 - fenoksykarbo-nyl-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 3, 8,0 g kaliumhydroksyd i pellets i 50 ml etylenglykol ble rørt ved 155°C inntil man fikk en klar oppløsning. Denne ble avkjølt, fortynnet med vann og den bi faseblanding man da fikk ble så ekstrahert tre ganger med kloroform. De samlede kloro-formekstrakter ble vasket forsiktig med vann og tørket hvoretter kloroformen ble fjernet, hvorved man fikk et fast residum. Dette ble omkrystallisert fra en aceton-heksanblanding og man fikk prismer, smp. 142-144°C av 1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin]. a. A mixture of 3.0 g of 1,3-dihydro-11-phenoxycarbonyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine] from Example 3, 8.0 g of potassium hydroxide in pellets in 50 ml of ethylene glycol was stirred at 155°C until a clear solution was obtained. This was cooled, diluted with water and the bi-phase mixture obtained was then extracted three times with chloroform. The combined chloroform extracts were carefully washed with water and dried, after which the chloroform was removed, whereby a solid residue was obtained. This was recrystallized from an acetone-hexane mixture and prisms were obtained, m.p. 142-144°C of 1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine].

Analyse:Analysis:

Beregnet' for<C>l8H19<NS>: 76,83%C, 6,80%H, 4,98%N, 11,39%S.Calculated for<C>18H19<NS>: 76.83%C, 6.80%H, 4.98%N, 11.39%S.

Funnet: 77,05%C, 6,84%H, 4,68%N, 11,26%S. Found: 77.05%C, 6.84%H, 4.68%N, 11.26%S.

Eksempel 5Example 5

En blanding av 2,8 g 1,3-dihydro-3-fenylspiro-[benzo-(c)thiofen] fra eksempel 4a, 1,4 g benzylklorid og 3,5 g natriumbikarbonat i 50 ml'dimetylformamid ble rørt ved 70°C i 2 timer. Vann ble tilsatt den avkjølte blandingen, og man fikk en tofaseblanding som ble ekstrahert fire ganger med metylenklorid. Metylenkloridekstraktet ble tørket og konsentrert i vakuum, hvorved man fikk et oljeaktig' residum som utkrystalliserte seg ved henstand. Produktet ble omkrystallisert fra en A mixture of 2.8 g of 1,3-dihydro-3-phenylspiro-[benzo-(c)thiophene] from Example 4a, 1.4 g of benzyl chloride and 3.5 g of sodium bicarbonate in 50 ml of dimethylformamide was stirred at 70° C for 2 hours. Water was added to the cooled mixture to give a biphasic mixture which was extracted four times with methylene chloride. The methylene chloride extract was dried and concentrated in vacuo, whereby an oily residue was obtained which crystallized on standing. The product was recrystallized from a

eter-heksanblanding og ga fine nåler, smp. 144-145°C av 1'-benzyl-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin]. ether-hexane mixture and gave fine needles, m.p. 144-145°C of 1'-benzyl-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine].

Analyse:Analysis:

Beregnet for C25<H>25NS: 80>,82%C, 6-,78%H, 3,78%N, 8,63%S.Calculated for C25<H>25NS: 80>.82%C, 6-.78%H, 3.78%N, 8.63%S.

Funnet: 60,81%C, 6,68%H, 3,66%N, 8,76%S. Found: 60.81%C, 6.68%H, 3.66%N, 8.76%S.

Eksempel 6Example 6

En blanding av 3,9 g 1,3-dihydro-3-fenylspiro-[benzo-(c)thiofen-1,4'-piperidin] fra eksempel 4, 3,4 g dibenzoyl-peroksyd, 4,0 g kaliumkarbonat i 60 ml benzen ble rørt ved A mixture of 3.9 g of 1,3-dihydro-3-phenylspiro-[benzo-(c)thiophene-1,4'-piperidine] from Example 4, 3.4 g of dibenzoyl peroxide, 4.0 g of potassium carbonate in 60 ml of benzene was stirred

65-70°C i 16 timer og deretter filtrert. Filtratet ble vasket65-70°C for 16 hours and then filtered. The filtrate was washed

og tørket, og oppløsningsmidlet fjernet i vakuum, noe som gaand dried, and the solvent removed in vacuo to give

et urent oljeaktig produkt. Dette ble kromatografert gjennom en silisiumdioksyd gelkolonne med metylenklorid som elueringsmiddel, hvorved man fikk 1<1->benzoyloksy-1,3-dihydro-3-fenyl-spiro- [benzo ( c) thiof en- 1 , 4 ' -piperidin ] . an impure oily product. This was chromatographed through a silica gel column with methylene chloride as eluent, whereby 1<1->benzoyloxy-1,3-dihydro-3-phenyl-spiro-[benzo(c)thiophene-1,4'-piperidine] was obtained.

Analyse:Analysis:

Beregnet for C25H23N02S: 74,78%C, 5,77%H, 3,48%N.Calculated for C25H23N02S: 74.78%C, 5.77%H, 3.48%N.

Funnet: 74,67%C, 5,82%H, 3,33%N. Found: 74.67%C, 5.82%H, 3.33%N.

Eksempel 7Example 7

En blanding av 0,6 g 1, 3'-dihydro-3-fenylspiro- [benzo (c) - thiofen-1,4<1->piperidin], eksempel 4, 0,7 g y-klor-4-fluorbutyro-fenonetylenketal, 0,5 g kaliumjodid og 0,5 g natriumbikarbonat i 15 ml dimetylformamid ble rørt ved 80°C i 16 timer. Reaksjonsblandingen ble avkjølt og fortynnet med metylenklorid. A mixture of 0.6 g of 1,3'-dihydro-3-phenylspiro-[benzo (c)-thiophene-1,4<1->piperidine], Example 4, 0.7 g of γ-chloro-4-fluorobutyro -phenoneethylene ketal, 0.5 g of potassium iodide and 0.5 g of sodium bicarbonate in 15 ml of dimethylformamide were stirred at 80°C for 16 hours. The reaction mixture was cooled and diluted with methylene chloride.

Den fortynnedé blandingen ble filtrert, og filtratet konsentrert i vakuum, hvorved man fikk en olje som utkrystalliserte seg ved avkjøling. Det faste produkt ble omkrystallisert fra en eter-pentanblanding og man fikk svakt brune krystaller, smp. 121-122°C av 1'-[3-(4-fluorbenzoyl)propyl]-l,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin]-etylenketal. Analyse: The diluted mixture was filtered, and the filtrate concentrated in vacuo, whereby an oil was obtained which crystallized on cooling. The solid product was recrystallized from an ether-pentane mixture and slightly brown crystals were obtained, m.p. 121-122°C of 1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine]-ethylene ketal. Analysis:

Beregnet for C3QH32<F>N02S:73,59%C, 6,59%H, 2,86%N.Calculated for C3QH32<F>N02S: 73.59%C, 6.59%H, 2.86%N.

Funnet: 73,81%C,' 6,33%H, 2,74%N. Found: 73.81%C,' 6.33%H, 2.74%N.

Eksempel 8Example 8

En prøve av oljen 1'-[3-(4-fluorbenzoyl)propyl]-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin]-etylenketal fra eksempel 7 ble rørt med et overskudd av 3N saltsyre i etanol i 16 timer. Overskuddet av syre og etanol ble fjernet i vakuum, ogresidumet oppløst i en blanding av 20% natriumhydroksyd og metylenklorid. Man fikk en tofaset blanding som ble hensatt for separasjon, og den organiske fase ble oppsamlet og tørket, hvoretter oppløsningsmidlet. ble. fjernet i vakuum, noe som ga en rødaktig olje som utkrystalliserte seg ved avkjøling. Det faste produktet ble omkrystallisert fra en eter-pentanblanding og man fikk krystaller som smeltet ved 118-120°C av l'-[3-(4-fluorbenzoyl)-propyl]-l,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin]. A sample of the oil 1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine]-ethylene ketal from Example 7 was stirred with an excess of 3N hydrochloric acid in ethanol for 16 hours. The excess of acid and ethanol was removed in vacuo, and the residue dissolved in a mixture of 20% sodium hydroxide and methylene chloride. A two-phase mixture was obtained which was set aside for separation, and the organic phase was collected and dried, after which the solvent. became. removed in vacuo to give a reddish oil which crystallized on cooling. The solid product was recrystallized from an ether-pentane mixture and crystals melting at 118-120°C of 1'-[3-(4-fluorobenzoyl)-propyl]-1,3-dihydro-3-phenylspiro-[benzo (c) thiophene-1,4'-piperidine].

Analyse:Analysis:

Beregnet for C28<H>2<g>FNOS: 75,47%C, 6,33%H, 3,14%N, 7,20%S. Funnet: 75, 74%C-, 6,45%H, 2,93%N, 7,21%S. Calculated for C28<H>2<g>FNOS: 75.47%C, 6.33%H, 3.14%N, 7.20%S. Found: 75, 74%C-, 6.45%H, 2.93%N, 7.21%S.

Eksempel 9Example 9

En prøve av 3-(4-klorfeny1)-1,3-dihydro-l'-metylspiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 2 ble behandlet som beskrevet i eksempel 3, hvorved man fikk 3-(4-klorfeny1)-1,3-dihydro-l'-fenoksykarbonylspiro-[benzo(c)thiofen-1,4'-piperidin] som et glassakti.g fast stoff. Dette ble kromatografert gjennom en silisiumdioksydgelkolonne med metylenklorid som elueringsmiddel, hvorved man fikk et rent, hvitt fast produkt, smp. 211-212°C. A sample of 3-(4-chlorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c)thiophene-1,4'-piperidine] from Example 2 was treated as described in Example 3, whereby one obtained 3-(4-Chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4'-piperidine] as a glass-active solid. This was chromatographed through a silica gel column with methylene chloride as eluent, whereby a pure, white solid product was obtained, m.p. 211-212°C.

Analyse:Analysis:

Beregnet for C25H22C1N02S: 68,81%C, 5,08%H, 3,21%N.Calculated for C25H22C1N02S: 68.81%C, 5.08%H, 3.21%N.

Funnet: 69,04%C, 5,03%H, 2,97%N. Found: 69.04%C, 5.03%H, 2.97%N.

Eksempel 10Example 10

En kald rørt oppløsning av 1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 4, og trietyl-amin i 50 ml kloroform ble dråpevis behandlet med en oppløsning av acetylklorid i kloroform, hvorved man fikk 1'-acetyl-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin]. A cold stirred solution of 1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine] from Example 4, and triethylamine in 50 ml of chloroform was treated dropwise with a solution of acetyl chloride in chloroform, whereby 1'-acetyl-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine] was obtained.

Eksempel 11Example 11

En oppløsning av 1'-acetyl-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 10 i tetrahydrofuran ble forsiktig behandlet med en rørt suspensjon av litiumaluminiumhydrid i tetrahydrofuran, hvorved man fikk l'-etyl-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin]. Eksempel 12 A solution of 1'-acetyl-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine] from Example 10 in tetrahydrofuran was gently treated with a stirred suspension of lithium aluminum hydride in tetrahydrofuran , whereby 1'-ethyl-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine] was obtained. Example 12

a. 13,3 ml bortrifluorideterat ble tilsatt en godt rørt oppløsning av 6,0 g 4-(2-fluorfeny1)-4-hydroksy-l-metylpiperidin, eksempel la, og 9 ml 4-metylbenzylmerkaptan i 13,3 ml iseddik. Etter tilsetning ble blandingen oppvarmet til 60-65°C i 2 timer. Overskudd av reagenser ble fjernet i vakuum ved 70°C, og man fikk et residum som ble rørt med 50 ml 2N saltsyre og 50 ml eter, hvorved man fikk et semifast produkt i'et resulterende intermediært lag. Dette stoff ble oppsamlet og omdannet til sin frie base med-20% natriumhydroksydoppløs-ning. Den frie basen ble omdannet til et hydrobromid som ble utkrystallisert fra en metanol-eterblanding, hvorved man fikk et hvitt fast stoff, smp. 182-184°C av 4-(2-fluorfeny1-1-metyl-4-(4-metylbenzylthio)-piperidinhydrobromid. a. 13.3 ml of boron trifluoroidetate was added to a well-stirred solution of 6.0 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine, example 1a, and 9 ml of 4-methylbenzyl mercaptan in 13.3 ml of glacial acetic acid. After addition, the mixture was heated to 60-65°C for 2 hours. Excess reagents were removed in vacuo at 70°C, and a residue was obtained which was stirred with 50 ml of 2N hydrochloric acid and 50 ml of ether, whereby a semi-solid product was obtained in the resulting intermediate layer. This substance was collected and converted to its free base with 20% sodium hydroxide solution. The free base was converted to a hydrobromide which was crystallized from a methanol-ether mixture to give a white solid, m.p. 182-184°C of 4-(2-fluorophenyl-1-methyl-4-(4-methylbenzylthio)-piperidine hydrobromide.

b. En-oppløsning av 0,7 g natriumhydrid i 50% mineralolje i 20 ml dimetylsulfoksyd ble i løpet av 5 min. tilsatt en blanding av 4,1 g 4-(2-fluorfeny1)-1-mety1-4-(4-metylbenzy1-thio)-piperidin, fri base av produktet fremstilt som beskrevet under avsnitt a ovenfor, i 15 ml dimetylsulfoksyd. Etter tilsetningen ble blandingen rørt i 30 minutter og så helt over i 100 ml isvann. Man fikk en tofaset blanding som ble filtrert og man oppsamlet et svakt brunt fast stoff som ble oppløst i diklormetan og så kolonnekromatografert på en aluminiumoksyd-kolon-ne med eter som elueringsmiddel. Det kromatograf erte produkt ble omkrystallisert fra en eter-heksanblanding, hvorved man fikk produktet, smp. 121-122°C av 1,3-dihydro-l'-mety1-3-(4-mety1fenyl)-spiro-[benzo(c)thiofen-1,4'-piperidin]. Analyse: b. A solution of 0.7 g of sodium hydride in 50% mineral oil in 20 ml of dimethylsulfoxide was in the course of 5 min. added a mixture of 4.1 g of 4-(2-fluorophenyl)-1-methyl-4-(4-methylbenzyl-thio)-piperidine, free base of the product prepared as described under section a above, in 15 ml of dimethylsulfoxide. After the addition, the mixture was stirred for 30 minutes and then poured into 100 ml of ice water. A two-phase mixture was obtained which was filtered and a light brown solid was collected which was dissolved in dichloromethane and then column chromatographed on an aluminum oxide column with ether as eluent. The chromatographed product was recrystallized from an ether-hexane mixture, whereby the product was obtained, m.p. 121-122°C of 1,3-dihydro-1'-methyl-3-(4-methylphenyl)-spiro-[benzo(c)thiophene-1,4'-piperidine]. Analysis:

Beregnet for C20<H>23NS: 77,62%C, 7,49%H, 4,53%N.Calculated for C20<H>23NS: 77.62%C, 7.49%H, 4.53%N.

Funnet: 77,63%C, 7,67%H, 4,35%N. Found: 77.63%C, 7.67%H, 4.35%N.

Eksempel 13Example 13

En oppløsning av 1,0 g 1,3-dihydro-l'-mety1-3-(4-metylfenyl)spiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 12 i 10 ml diklormetan ble tilsatt en rørt suspensjon av 0,6 g fenylklorformat og 0,2 g natriumbikarbonat i 20 ml diklormetan. Etter tilsetning ble blandingen rørt ved romtemperatur i 24 timer og deretter filtrert, fortynnet med 50 ml metylenklorid, ekstrahert med en 10% natriumhydroksyd-oppløsning og så ekstrahert med vann og så tørket og deretter filtrert. Oppløsningsmidlet ble fjernet og man fikk en olje. Denne ble kolonnekromatografert på en silisiumdioksydgel/ metylenkloridkolonne med metylenklorid som elueringsmiddel, hvorved man fikk et hvitt voluminøst fast stoff som ble omkrystallisert fra en benzen-heksanblanding, hvorved man fikk produktet, smp. 179-180°C av 1,3-dihydro-3-(4-metylenfeny1)-1'-fenoksykarbonylspiro-[benzo(c)thiofen-1,4'-piperidin]. A solution of 1.0 g of 1,3-dihydro-1'-methyl-3-(4-methylphenyl)spiro-[benzo(c)thiophene-1,4<1->piperidine] from Example 12 in 10 ml of dichloromethane was added to a stirred suspension of 0.6 g of phenylchloroformate and 0.2 g of sodium bicarbonate in 20 ml of dichloromethane. After addition, the mixture was stirred at room temperature for 24 hours and then filtered, diluted with 50 ml of methylene chloride, extracted with a 10% sodium hydroxide solution and then extracted with water and then dried and then filtered. The solvent was removed and an oil was obtained. This was column chromatographed on a silica gel/methylene chloride column with methylene chloride as eluent, whereby a white voluminous solid was obtained which was recrystallized from a benzene-hexane mixture, whereby the product was obtained, m.p. 179-180°C of 1,3-dihydro-3-(4-methylenephenyl)-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4'-piperidine].

Analyse:Analysis:

Beregnet for C26H25N02S:75,15%C, 6,06%H, 3,37%N.Calculated for C26H25N02S: 75.15%C, 6.06%H, 3.37%N.

Funnet: 75,24%C, 6,10%H, 3,16%N. Found: 75.24%C, 6.10%H, 3.16%N.

Eksempel 14Example 14

En blanding av 0,5 g 1,3-dihydro-3-fenylspiro-[benzo-(c)thiofen-1,4'-piperidin] fra eksempel 4, 0,4 g cyklopropyl-karbonylklorid og 1,0 g natriumbikarbonat i 20 ml diklormetan ble rørt ved romtemperatur i 16 timer. Blandingen ble filtrert og filtratet konsentrert til tørrhet. Residumet ble ført gjennom en silisiumdioksydgel/eterkolonne med eter som elueringsmiddel, og man fikk rent 1'-cyklopropylkarbonyl-1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1,4<1->piperidin]. A mixture of 0.5 g of 1,3-dihydro-3-phenylspiro-[benzo-(c)thiophene-1,4'-piperidine] from Example 4, 0.4 g of cyclopropyl carbonyl chloride and 1.0 g of sodium bicarbonate in 20 ml of dichloromethane was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate concentrated to dryness. The residue was passed through a silica gel/ether column with ether as eluent, and pure 1'-cyclopropylcarbonyl-1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,4<1->piperidine] was obtained.

Analyse:Analysis:

Beregnet for C22H23NOS: 75,60%C, 6,63%H, 4,01%N.'Calculated for C22H23NOS: 75.60%C, 6.63%H, 4.01%N.'

Funnet: 75,56%C, 6,69%H, 3,71%N. Found: 75.56%C, 6.69%H, 3.71%N.

Eksempel 15Example 15

En blanding av 14,4 g 3-(4-klorfenyl)-1,3-dihydro-l'-fenoksykarbonylspiro-[benzo(c)thiofen-1,4<1->piperidin], eksempel 9, 220 ml etylenglykol og 35,3 g kaliumhydroksydpellets ble behandlet som beskrevet i eksempel 4, hvorved man fikk et gulaktig hvitt krystallinsk fast stoff. Dette ble utrørt i pentan og hensatt ved 0°C i .16 timer før blandingen ble filtrert, hvorved man fikk et hvitt pulver som ble omkrystallisert fra aceton og heksan hvorved man fikk produktet, smp. 138-140°C av 3-(4-klorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]. Analyse: Beregnet for C18H18<C>1NS: 68,46%C, 5,75%H, 4,44%N, 11,23%C1. Funnet: 68,48%C, 5,81%H, 4,34%N, 11,27%C1. Eksempel 16 A mixture of 14.4 g of 3-(4-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4<1->piperidine], Example 9, 220 ml of ethylene glycol and 35.3 g of potassium hydroxide pellets were treated as described in example 4, whereby a yellowish white crystalline solid was obtained. This was stirred in pentane and left at 0°C for .16 hours before the mixture was filtered, giving a white powder which was recrystallized from acetone and hexane to give the product, m.p. 138-140°C of 3-(4-chlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4<1->piperidine]. Analysis: Calculated for C18H18<C>1NS: 68.46%C, 5.75%H, 4.44%N, 11.23%C1. Found: 68.48%C, 5.81%H, 4.34%N, 11.27%C1. Example 16

1,4 g natriumbikarbonat og 1,4 g kaliumjodid ble tilsatt en blanding av 2,0 g 3-(4-klorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin] , eksempel 15, og 2,0 g y-klor-4-fluorbutyrofenonetylenketal i 20 ml dimetylformamid. Blandingen ble oppvarmet under røring ved 80-85°C .i 17 timer. Den ble så avkjølt til romtemperatur og fortynnet med 50 ml kloroform. Den fortynnede oppløsning ble konsentrert til tørr-het, og residumet delt mellom 100 ml metylenklorid og 50 ml vann. De to lagene ble ristet og så hensatt for separasjon. Det organiske laget ble vasket først med vann og så med en mettet natriumkloridoppløsning og så tørket, hvorved man fikk en olje. Denne ble kolonnekromatografert på en aluminiumoksyd-• ' .kolonne med eter, hvorved man fikk en klar olje av 3-(4-klor-fenyl)-1<1->[3-(4-fluorbenzoyl)propyl]-1,3-dihydrospiro-[benzo-(c)thiofen-1,4'-piperidin]-etylenketal. 1.4 g of sodium bicarbonate and 1.4 g of potassium iodide were added to a mixture of 2.0 g of 3-(4-chlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine], example 15, and 2.0 g of γ-chloro-4-fluorobutyrophenoneethylene ketal in 20 ml of dimethylformamide. The mixture was heated with stirring at 80-85°C for 17 hours. It was then cooled to room temperature and diluted with 50 ml of chloroform. The dilute solution was concentrated to dryness and the residue partitioned between 100 ml of methylene chloride and 50 ml of water. The two layers were shaken and then set aside for separation. The organic layer was washed first with water and then with a saturated sodium chloride solution and then dried to give an oil. This was column chromatographed on an alumina column with ether, whereby a clear oil of 3-(4-chloro-phenyl)-1<1->[3-(4-fluorobenzoyl)propyl]-1,3 -dihydrospiro-[benzo-(c)thiophene-1,4'-piperidine]-ethylene ketal.

Analyse:Analysis:

Beregnet for C3QH31C1FN02S: 68,76%C, 5,96%H, 2,6%N. Funnet: 68,63%C, 5,89%H, 2,71%N. Calculated for C3QH31C1FN02S: 68.76%C, 5.96%H, 2.6%N. Found: 68.63%C, 5.89%H, 2.71%N.

Eksempel 17Example 17

En blanding av 2,0 g 3-(4-klorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin] eksempel 15, 0,7 g klormetyl-, cyklopropan, 1,4 g kaliumjodid og 1,4 g natriumbikarbonat i 20 ml dimetylformamid ble oppvarmet under røring til 80-85°C i 17 timer. Blandingen ble så avkjølt til romtemperatur og så fortynnet med 75 ml vann og 30 ml metylenklorid. Den vandige fasen ble ekstrahert to ganger med metylenklorid og alle mety-lenkloridoppløsninger ble slått sammen. Den samlede oppløsning ble så vasket først med'vann og så med mettet natriumklorid-oppløsning og så tørket, hvorved man fikk en klar olje. Denne ble kromatografert på en aluminiumoksydkolonne med eter, hvorved man fikk en olje med forbedret renhet. Denne oljen ble omdannet til sitt maleinsyresalt som ble omkrystallisert fra aceton og. eter hvorved man fikk saltet, smp. 217,5-218°C av. 3-(4-klorfenyl)-1<1->cyklopropylmety1-1,3-dihydrospiro-[benzo-(c)thiofen-1,4'-piperidin]-rnaleat. A mixture of 2.0 g of 3-(4-chlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine] Example 15, 0.7 g of chloromethyl-, cyclopropane, 1,4 g of potassium iodide and 1.4 g of sodium bicarbonate in 20 ml of dimethylformamide were heated with stirring to 80-85°C for 17 hours. The mixture was then cooled to room temperature and then diluted with 75 ml of water and 30 ml of methylene chloride. The aqueous phase was extracted twice with methylene chloride and all methylene chloride solutions were combined. The combined solution was then washed first with water and then with saturated sodium chloride solution and then dried to give a clear oil. This was chromatographed on an alumina column with ether, whereby an oil of improved purity was obtained. This oil was converted to its maleic acid salt which was recrystallized from acetone and. ether by which the salt was obtained, m.p. 217.5-218°C off. 3-(4-Chlorophenyl)-1<1->cyclopropylmethyl-1,3-dihydrospiro-[benzo-(c)thiophene-1,4'-piperidine]-manaleate.

Analyse:Analysis:

Beregnet for C22H24C1NS ■ C H404 :'■ 64, 25%C, 5,81%H, 2,88%N, 7,30%C1. Funnet: . 64,13%C, 5,82%H, 2,77%N, 7,36%C1. Calculated for C22H24C1NS ■ C H4O4 :'■ 64, 25%C, 5.81%H, 2.88%N, 7.30%C1. Found: . 64.13% C, 5.82% H, 2.77% N, 7.36% Cl.

Eksempel 18Example 18

En reaksjonsblanding av 4,2 g 3-(4-klorfenyl)-1'-[3-(4-fluorbenzoyl)propyl]-l,3-dihydrospiro-[benzo(c)thiofen-.1,4'-piperidinj-etylenketal, uren olje fra eksempel 16, og 22 ml 3N saltsyre i 60 ml etanol ble rørt ved romtemperatur i 20 timer og så avkjølt til 0°C i ytterligere 20 timer. Et gummiaktig bunnfall ble fjernet ved filtrering, .og filtratet ble under-kastet roterende fordampning ved 50°C, hvorved man fikk et orange residum. Dette ble delt mellom 50 ml .20% natriumhydroksyd og 100 ml av en 1:1 blanding av eter og metylenklorid. Lagene ble skilt, og det vandige lag ble ekstrahert med ytterligere 40 ml av forannevnte eter. De organiske deler ble slått sammen/og disse ble fortynnet med 50 ml eter og så vasket med vann og en mettet natriumkloridoppløsning, tørket og fordampet, hvorved man fikk en klar orange olje. Denne ble kromatografert på en silisiumdioksydgelkolonne med et elueringsmiddel av 5% metanol i metylenklorid, hvorved man fikk en ren olje. Denne ble så oppløs.t i eter og omdannet til sitt hydrobromidsalt som var et hvitt pulver. Dette ble omkrystallisert to ganger fra en metanol-eterblanding, og man fikk saltet, smp. 240-241°C av 3- (4-klorfenyl)-11-[3-(4-fluorbenzoyl)propyl]-l,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-hydrobromid. A reaction mixture of 4.2 g of 3-(4-chlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiophene-.1,4'-piperidinj- ethylene ketal, crude oil from Example 16, and 22 ml of 3N hydrochloric acid in 60 ml of ethanol were stirred at room temperature for 20 hours and then cooled to 0°C for a further 20 hours. A gummy precipitate was removed by filtration, and the filtrate was subjected to rotary evaporation at 50°C, whereby an orange residue was obtained. This was partitioned between 50 ml of 20% sodium hydroxide and 100 ml of a 1:1 mixture of ether and methylene chloride. The layers were separated and the aqueous layer was extracted with an additional 40 ml of the aforementioned ether. The organic parts were combined/and these were diluted with 50 ml of ether and then washed with water and a saturated sodium chloride solution, dried and evaporated to give a clear orange oil. This was chromatographed on a silica gel column with an eluent of 5% methanol in methylene chloride, whereby a pure oil was obtained. This was then dissolved in ether and converted to its hydrobromide salt, which was a white powder. This was recrystallized twice from a methanol-ether mixture, and the salt was obtained, m.p. 240-241°C of 3-(4-chlorophenyl)-11-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiophene-1,4<1->piperidine]- hydrobromide.

Analyse:Analysis:

Beregnet for C18H22C1FN0S•HBr: 59,96%C, 5,03%H, 2,05%N.Calculated for C18H22C1FN0S•HBr: 59.96%C, 5.03%H, 2.05%N.

Funnet: 60,03%C, 4,85%H, 2,36%N. Eksempel 19 Found: 60.03%C, 4.85%H, 2.36%N. Example 19

a. En reaksjonsblanding av 10,0 g 4-(2-fluorfenyl)-4- hydroksy-l-metylpiperidin, eksempel la, 17,5 ml 3,4-diklor-benzylmerkaptan og 22 ml bortrifluoridetérat i 22 ml iseddik ble rørt ved 60-65°C i 16 timer. Oppløsningsmidlet ble deretter fjernet under redusert trykk, og residumet behandlet med en blanding av eter og IN saltsyre. Blandingen ble rørt ved 0°C a. A reaction mixture of 10.0 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine, Example 1a, 17.5 ml of 3,4-dichloro-benzyl mercaptan and 22 ml of boron trifluoride etherate in 22 ml of glacial acetic acid was stirred at 60-65°C for 16 hours. The solvent was then removed under reduced pressure and the residue treated with a mixture of ether and 1N hydrochloric acid. The mixture was stirred at 0°C

i 2 timer og det resulterende hvite krystallinske bunnfall ble for 2 hours and the resulting white crystalline precipitate was

oppsamlet ved filtrering. Det ble så omkrystallisert fra en aceton-eterblanding og man fikk fargeløse nåler, smp. 188-190°C av 4-(3,4-diklorbenzylthio)-4^(2-fluorfenyl)-1-metylpiperidin-hydroklorid. collected by filtration. It was then recrystallized from an acetone-ether mixture and colorless needles were obtained, m.p. 188-190°C of 4-(3,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine hydrochloride.

b. 8,2 g av 4-(3,4-diklorbenzylthio)-4-(2-fluorfeny1) - 1-metylpiperidin, fri base av produktet fra avsnitt a, i 20 ml dimetylsulfoksyd ble forsiktig tilsatt i løpet av 20 minutter til en avkjølt oppløsning av natrium-metylsulfinylmetid fremstilt ved å oppvarme 1,2 g natriumhydrid (50%) i 50 ml dimetylsulfoksyd ved 80°C.i en halv time. Etter tilsetningen ble blandingen rørt.ved romtemperatur i 30 minutter og så tilsatt vann. Man fikk en tofaset blanding som ble ekstrahert med metylenklorid, og metylerikloridekstraktet ble tørket og konsentrert b. 8.2 g of 4-(3,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine, free base of the product from section a, in 20 ml of dimethylsulfoxide was carefully added over 20 minutes to a cooled solution of sodium methylsulfinyl methide prepared by heating 1.2 g of sodium hydride (50%) in 50 ml of dimethyl sulfoxide at 80°C. for half an hour. After the addition, the mixture was stirred at room temperature for 30 minutes and then water was added. A biphasic mixture was obtained which was extracted with methylene chloride, and the methylene chloride extract was dried and concentrated

hvorved man fikk en brun olje som utkrystalliserte seg ved henstand. Produktet ble omdannet i eter til sitt maleinsyresalt whereby a brown oil was obtained which crystallized on standing. The product was converted in ether to its maleic acid salt

som ble omkrystallisert fra en aceton-eterblanding og man fikk saltet, smp. 212-213°C av 3-(3,4-diklorfeny1)-1,3-dihydro-l•-metylspiro-[benzo(c)thiofen-1,41-piperidin]-rnaleat. which was recrystallized from an acetone-ether mixture and the salt was obtained, m.p. 212-213°C of 3-(3,4-dichlorophenyl)-1,3-dihydro-1•-methylspiro-[benzo(c)thiophene-1,41-piperidine]-rnalate.

Analyse:Analysis:

Beregnet for CigHigCl2NS • C4H40'4: 57, 50%C, 4,83%H, 2,95%N, 14,76%0 Funnet: 57,75%C, 4,81%H, 2,72%N, 14,49%0 Eksempel 20 Calculated for CigHigCl2NS • C4H40'4: 57, 50%C, 4.83%H, 2.95%N, 14.76%0 Found: 57.75%C, 4.81%H, 2.72%N , 14.49%0 Example 20

a. En prøve av 2-brom-1,4-difluorbenzen ble ifølge fremgangsmåten fra eksempel la behandlet slik at man fikk fremstilt 4-(2,5-difluorfenyl)-4-hydroksy-l-metylpiperidin, som ble omdannet til sitt maleinsyresalt som igjen ble omkrystallisert fra en aceton-eterblanding og man fikk det rene saltet, smp. 163-165°C. a. A sample of 2-bromo-1,4-difluorobenzene was treated according to the procedure from example la so that 4-(2,5-difluorophenyl)-4-hydroxy-1-methylpiperidine was produced, which was converted to its maleic acid salt which was again recrystallized from an acetone-ether mixture and the pure salt was obtained, m.p. 163-165°C.

b. En blanding av 4-(2,5-difluorfenyl)-4-hydroksy-l-metyl-piperidin, fri base av produktet under avsnitt a, 4 ml bortrifluorideterat, 5 ml benzylmerkaptan og-5 ml iseddik ble rørt ved 65°C i 16 timer. Overskudd av syre ble fjernet under redusert trykk og residumet utlignet med 0,5N saltsyre og eter og den resulterende oppløsning■ble'rørt ved 10-20°C i 4 timer. Det resulterende krystallinske bunnfall ble oppsamlet ved filtrering, gjort basisk og'ekstrahert med eter hvorved man fikk det forønskede produkt som en olje. Denne ble omdannet til b. A mixture of 4-(2,5-difluorophenyl)-4-hydroxy-1-methyl-piperidine, free base of the product under section a, 4 ml of boron trifluoride etherate, 5 ml of benzyl mercaptan and -5 ml of glacial acetic acid was stirred at 65° C for 16 hours. Excess acid was removed under reduced pressure and the residue balanced with 0.5N hydrochloric acid and ether and the resulting solution was stirred at 10-20°C for 4 hours. The resulting crystalline precipitate was collected by filtration, basified and extracted with ether to give the desired product as an oil. This was transformed into

■ sitt maleinsyresalt som ble omkrystallisert fra en aceton-eterblanding og man fikk prismer, smp. 164-166°C av 4-benzylthio- ■ its maleic acid salt, which was recrystallized from an acetone-ether mixture and prisms were obtained, m.p. 164-166°C of 4-benzylthio-

4-(2,5-diflyorfenyl)-1-metylpiperidinmaleat.4-(2,5-difluorophenyl)-1-methylpiperidine maleate.

c. En oppløsning av natriummetylsulfinylmetid som var fremstilt ved å oppvarme 250 mg natriumhydrid (50% dispersjon vasket med bentan) i 10 ml dimetylsulfoksyd ved 80°C i 30 minutter, ble i løpet av 5 minutter ved romtemperatur tilsatt en blanding av 4-benzylthio-4-(2,5-difluorfenyl)-1-metylpiperidin fri base av produktet fra avsnitt b, i 5 ml dimetylsulfoksyd. Etter tilsetning ble blandingen rørt ved ' romtemperatur i 30 minutter og så helt over i 50 g isvann. Blandingen ble ekstrahert 3 ganger med metylenklorid og de samlede ekstraktér vasket med vann og tørket. Metylenkloriden ble så fjernet under vakuum og man fikk et fast residum. Dette ble omkrystallisert fra en eter-pentanblanding'og man fikk granulære krystaller, smp. 136-137°C av 6-fluor-1,3-dihydro-l'-metyl-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin]. c. A solution of sodium methylsulfinyl methide which was prepared by heating 250 mg of sodium hydride (50% dispersion washed with bentane) in 10 ml of dimethylsulfoxide at 80°C for 30 minutes was added over 5 minutes at room temperature to a mixture of 4-benzylthio -4-(2,5-difluorophenyl)-1-methylpiperidine free base of the product from section b, in 5 ml of dimethylsulfoxide. After addition, the mixture was stirred at room temperature for 30 minutes and then poured into 50 g of ice water. The mixture was extracted 3 times with methylene chloride and the combined extracts washed with water and dried. The methylene chloride was then removed under vacuum and a solid residue was obtained. This was recrystallized from an ether-pentane mixture and granular crystals were obtained, m.p. 136-137°C of 6-fluoro-1,3-dihydro-1'-methyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine].

Analyse:Analysis:

Beregnet for C19H20FNS: 72,81.%C, 6,42%H, 4,47%N, 6,06%F, 10,23%S Funnet: 72,52%C, 6,46%H, 4,27%N, 5/88%F, 10,49%S Eksempel 21 Calculated for C19H20FNS: 72.81%C, 6.42%H, 4.47%N, 6.06%F, 10.23%S Found: 72.52%C, 6.46%H, 4, 27%N, 5/88%F, 10.49%S Example 21

En blanding av 0,3 g 6-fluor-1,3-dihydro-l<1->mety1-3-fenylspiro-[benzo(c)thiofen-1,4'-piperidin] og 0,3 g fenylklorformat i 10 ml metylenklorid ble rørt ved romtemperatur i 16 timer og så tilsatt vann, og deretter vasket med 10% natrium-hydroksydoppløsning og tørket.Reaksjonsblandingen ble konsentrert under vakuum hvorved man fikk en viskøs olje som utkrystalliserte seg ved henstand. Det faste produktet ble. omkrystallisert fra en eter-pentanblanding og man fikk prismer, smp. 156-158°C- av 6-fluor-1,3-dihydro-3-feny1-1<1->fenoksykarbo-nylspiro- [benzo(c)thiofen-1,41-piperidin]. A mixture of 0.3 g of 6-fluoro-1,3-dihydro-1<1->methyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine] and 0.3 g of phenylchloroformate in 10 ml of methylene chloride was stirred at room temperature for 16 hours and then water was added, and then washed with 10% sodium hydroxide solution and dried. The reaction mixture was concentrated under vacuum whereby a viscous oil was obtained which crystallized on standing. The solid product was. recrystallized from an ether-pentane mixture and prisms were obtained, m.p. 156-158°C- of 6-fluoro-1,3-dihydro-3-phenyl-1<1->phenoxycarbonylspiro-[benzo(c)thiophene-1,41-piperidine].

Analyse:Analysis:

Beregnet for C25H22FN02S: 71,57%C, 5,29%H, 3,'34%N.Calculated for C25H22FN02S: 71.57%C, 5.29%H, 3.34%N.

Funnet: 71,65%C, 5,38%H, 3,15%N. Found: 71.65%C, 5.38%H, 3.15%N.

Eksempel 2 2Example 2 2

En oppløsning av 2,5 g 3-(3,4-diklorfenyl)-1,3-dihydro-1<1->metylspiro-[benzo(c)thiofen-1,4'-piperidin], fri base av produktet fra eksempel. 19, og 1,3 g f eny lklorf orma t i 30 ml metylenklorid ble rørt ved romtemperatur i 16 timer. Oppløs-ningen ble vasket suksessivt med fortynnet natriumhydroksyd og vann og deretter tørket, hvorved man fikk et krystallinsk produkt. Dette ble omkrystallisert fra en aceton-pentanblanding og man fikk fine nåler, smp. 200-202°C, av 3-(3,4-diklorfeny1)-1,3-dihydro-l'-fenoksykarbonylspiro-[benzo(c)thiofen-1,4'-piperidin]. A solution of 2.5 g of 3-(3,4-dichlorophenyl)-1,3-dihydro-1<1->methylspiro-[benzo(c)thiophene-1,4'-piperidine], free base of the product from Example. 19, and 1.3 g of phenylchloroform in 30 ml of methylene chloride was stirred at room temperature for 16 hours. The solution was washed successively with dilute sodium hydroxide and water and then dried to give a crystalline product. This was recrystallized from an acetone-pentane mixture and fine needles were obtained, m.p. 200-202°C, of 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4'-piperidine].

Analyse:Analysis:

Beregnet for C25H21C12N02S: 63,83%C, 4,50%H, 2,98%N.Calculated for C25H21C12N02S: 63.83%C, 4.50%H, 2.98%N.

Funnet: 63,71%C, 4,56%H, 2,93%N. Eksempel 23 Found: 63.71%C, 4.56%H, 2.93%N. Example 23

a. 82 ml bortrifluorideterat ble tilsatt en blanding av 30,0 g 4-(2-fluorfenyl)-4-hydroksy-l-metyl-piperidin fra eksempel la og 82 ml 2-metylbenzylmerkaptan. Oppløsningen ble rørt og oppvarmet ved 75°C i 6 timer og overskuddet av reagenset ble så avdéstillert mellom 80-100°C. Den gjenværende ■ oljen i kolben ble utrørt med 250 ml 2N saltsyre og 500 ml eter i en time, hvoretter man tilsatte 1500 ml is slik at det dannes en suspensjon. Denne ble rørt i ytterligere 1 time og filtrert, hvorved man fikk- et hvitt fast stoff som' ble vasket med eter og lufttørket. Produktet, ble omkrystallisert fra metanol-aceton-eter, og man fikk produktet 4-(2-fluorfenyl)-1-mety1-4-(2-metylbenzylthio)piperidinhydroklorid. En elemen-tæranalyseprøve ble ytterligere' omkrystallisert fra aceton-eter og man fikk en prøve med konstant smeltepunkt på 206-208°C. Analyse: a. 82 ml of boron trifluoride etherate was added to a mixture of 30.0 g of 4-(2-fluorophenyl)-4-hydroxy-1-methyl-piperidine from example 1a and 82 ml of 2-methylbenzyl mercaptan. The solution was stirred and heated at 75°C for 6 hours and the excess reagent was then distilled off between 80-100°C. The remaining ■ oil in the flask was stirred with 250 ml of 2N hydrochloric acid and 500 ml of ether for one hour, after which 1500 ml of ice was added so that a suspension was formed. This was stirred for a further 1 hour and filtered, whereby a white solid was obtained which was washed with ether and air dried. The product was recrystallized from methanol-acetone-ether, and the product 4-(2-fluorophenyl)-1-methyl-4-(2-methylbenzylthio)piperidine hydrochloride was obtained. An elemental analysis sample was further recrystallized from acetone-ether and a sample with a constant melting point of 206-208°C was obtained. Analysis:

Beregnet, for C2QH24FNS•HC1: 65,64%C, 6,89%H, 3,83%N.Calculated, for C2QH24FNS•HC1: 65.64%C, 6.89%H, 3.83%N.

Funnet: 65, 46%C, 6,82%'H, 3,55%N. Found: 65, 46%C, 6.82%'H, 3.55%N.

b. 0,73 g natriumhydrid,. 50% i mineralolje ble renset ved behandling med heksan. Det rensede natriumhydrid ble tilsatt 20 ml dimetylsulfoksyd, og oppløsningen oppvarmet' på et oljebad ved 80-90°C i 30 minutter. Oppløsningen ble avkjølt til romtemperatur og man tilsatte i løpet av '5 minutter 4,05 g 4-(2-fluorfenyl)-1-mety1-4-(2-metylbenzylthio)piperidin fra eksempel 23a i 15 ml dimetylsulfoksyd. Reaksjonsblandingen ble rørt i 30 min., og så helt over i 100 ml isvann og filtrert. Det resulterende lysebrune faste stoff ble oppløst i diklormetan og kr<p>matografert på en Al-jO^/eter kolonne (eluering med eter), smp. 132-143°C. Prøven ble omkrystallisert fra eter til heksan og man fikk fremstilt 1,3-dihydro-l<1->metyl-3-(2-mety1fenyl)spiro-[benzo(c)thiofen-1,4<1->piperidin], smeltepunkt 132-134°C. b. 0.73 g of sodium hydride. 50% in mineral oil was purified by treatment with hexane. The purified sodium hydride was added to 20 ml of dimethylsulfoxide, and the solution was heated in an oil bath at 80-90°C for 30 minutes. The solution was cooled to room temperature and 4.05 g of 4-(2-fluorophenyl)-1-methyl-4-(2-methylbenzylthio)piperidine from example 23a in 15 ml of dimethylsulfoxide was added over 5 minutes. The reaction mixture was stirred for 30 min., and then poured into 100 ml of ice water and filtered. The resulting light brown solid was dissolved in dichloromethane and chromatographed on an Al-jO 4 /ether column (elution with ether), m.p. 132-143°C. The sample was recrystallized from ether to hexane and 1,3-dihydro-1<1->methyl-3-(2-methylphenyl)spiro-[benzo(c)thiophene-1,4<1->piperidine] was produced, melting point 132-134°C.

Analyse:Analysis:

Beregnet for C^H^NS: •77, 62%C, 7,49%H, 4,53%N.Calculated for C^H^NS: •77, 62%C, 7.49%H, 4.53%N.

Funnet: 77,63%C, 7,67%H, 4,35%N. Found: 77.63%C, 7.67%H, 4.35%N.

Eksemepl 24Example 24

En suspensjon av 3-(3 . 4-diklorfenyl)-1,3-dihydro-l1-fenoksykarbonylspiro-[benzo(c)thiofen-1,4'-piperidin] (2,35 g) , 7,0 g kaliumhydroksyd (85%) i 30 ml etylenglykol ble rørt ved 160°C i 30 minutter. Blandingen ble avkjølt, fortynnet med vann og ekstrahert med 300 ml porsjoner av diklormetan. Etter tørking over magnesiumsulfat og fordamping i vakuum, ble det urene aminet omdannet til et krystallinsk maleat i eter. Omkrystallisering fra metanol og eter ga rombiske krystaller av 3-(3,4-diklorfeny1)-1,3-dihydrospiro-[benzo(c)thiofen-1,41 - piperidin]-maleat, smp. 192-193°C. A suspension of 3-(3.4-dichlorophenyl)-1,3-dihydro-11-phenoxycarbonylspiro-[benzo(c)thiophene-1,4'-piperidine] (2.35 g), 7.0 g of potassium hydroxide ( 85%) in 30 ml of ethylene glycol was stirred at 160°C for 30 minutes. The mixture was cooled, diluted with water and extracted with 300 ml portions of dichloromethane. After drying over magnesium sulfate and evaporation in vacuo, the impure amine was converted to a crystalline maleate in ether. Recrystallization from methanol and ether gave rhombic crystals of 3-(3,4-dichlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,41-piperidine]-maleate, m.p. 192-193°C.

Analyse:Analysis:

Beregnet for C18H17Cl2NS'C4H404:56,65%C, 4,'54%H, 3,00%N, 15,20%C1. Funnet: 56,75%C, 4,51%H, 2,88_%N, 14,91%C1. Calculated for C18H17Cl2NS'C4H4O4: 56.65%C, 4.'54%H, 3.00%N, 15.20%C1. Found: 56.75%C, 4.51%H, 2.88_%N, 14.91%C1.

Eksempel 25Example 25

En blanding av 1,5 g av den frie basen 3-(3,4-diklor-fenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 24, 1,3 g yklorbutyrofenonetylenketal, 0,9 g kaliumjodid, 0,9 g natriumbikarbonat i 15 ml vannfri dimetylformamid ble rørt ved 80°C i 16 timer. Blandingen ble fortynnet med isvann og ekstrahert tre ganger med CH2C12. Oppløsningen ble tørket over kaliumkarbonat og konsentrert i vakuum til et olje- . aktig residum. Rensing ble utført ved kolonnekromatografi på aluminiumoksyd med eter som elueringsmiddel, og ved behandling med- eter-HBr fikk man et krystallinsk hydrobromid ved samtidig. spalting av ketalringen. Omkrystallisering av det granulære hydrobromid fra metanol/eter ga fargeløse krystaller av 3-(3,4-diklorfényl)-1<1->[3-(4-fluorbenzoyl)-propyl]-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-hydrobromid. A mixture of 1.5 g of the free base 3-(3,4-dichloro-phenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine] from Example 24, 1,3 g ychlorobutyrophenoneethylene ketal, 0.9 g of potassium iodide, 0.9 g of sodium bicarbonate in 15 ml of anhydrous dimethylformamide was stirred at 80°C for 16 hours. The mixture was diluted with ice water and extracted three times with CH 2 Cl 2 . The solution was dried over potassium carbonate and concentrated in vacuo to an oil. sticky residue. Purification was carried out by column chromatography on aluminum oxide with ether as eluent, and by treatment with ether-HBr a crystalline hydrobromide was obtained at the same time. cleavage of the ketal ring. Recrystallization of the granular hydrobromide from methanol/ether gave colorless crystals of 3-(3,4-dichlorophenyl)-1<1->[3-(4-fluorobenzoyl)-propyl]-1,3-dihydrospiro-[benzo(c )thiophene-1,4<1->piperidine]-hydrobromide.

Analyse:Analysis:

Beregnet for C2gH26Cl2FNOS•HBr: 56,47%C, 4,57%H, 2,23%N.Calculated for C2gH26Cl2FNOS•HBr: 56.47%C, 4.57%H, 2.23%N.

Funnet: 56, 43%C,- 4,59%H, 2,31%N. Found: 56, 43%C,- 4.59%H, 2.31%N.

Eksempel 26Example 26

En blanding av den frie basen 3-( 3,4-diklorfenyl)-1, 3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 24 (2,Og) av y-klor-4-fluorbutyrofenonetylenketal, 0,9 g natrium bikarbonat og 0,9 g kaliumjodid i 15 ml vannfri DMF ble rørt ved.80°C i 16 timer. Den avkjølte blanding ble fortynnet med vann og eter og lagene ble skilt. Den organiske oppløsning ble vasket med vann, tørket over magnesiumsulfat og konsentrert til et oljeaktig residum i vakuum. Rensing av råproduktet ble utført ved gjennomføring av en kort aluminium/eter-kolonne. Eluering med eter ga en blekt gul olje som ble omdannet til A mixture of the free base 3-(3,4-dichlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine] from Example 24 (2,Og) of γ-chloro-4 -fluorobutyrophenoneethylene ketal, 0.9 g of sodium bicarbonate and 0.9 g of potassium iodide in 15 ml of anhydrous DMF were stirred at 80°C for 16 hours. The cooled mixture was diluted with water and ether and the layers were separated. The organic solution was washed with water, dried over magnesium sulfate and concentrated to an oily residue in vacuo. Purification of the crude product was carried out by passing through a short aluminium/ether column. Elution with ether gave a pale yellow oil which was converted to

'et krystallinsk maleat i eter. Omkrystallisering fra aceton-eter ga granulære krystaller, smp.. 116-119°C av 3-(3,4-diklorfenyl)-1<1->[3-(4-fluorbenzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-etylenketalmaleat. 'a crystalline maleate in ether. Recrystallization from acetone-ether gave granular crystals, mp 116-119°C of 3-(3,4-dichlorophenyl)-1<1->[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro- [Benzo(c)thiophene-1,4<1->piperidine]-ethylene ketal maleate.

Analyse: Beregnet for C30H30Cl2FNO2S•C4H404: 60,52%C, 5,08%H, 2,08%N. Funnet:. 60,53%C, 5,05%H, 1,86%N. Eksempel 2 7 Analysis: Calculated for C30H30Cl2FNO2S•C4H404: 60.52%C, 5.08%H, 2.08%N. Found: 60.53%C, 5.05%H, 1.86%N. Example 2 7

a. En blanding av 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperidin fra eksempel la (10,5 g), 10 g p-fluorbenzyl-merkaptan, 18 ml bortrifluorideterat og 10 ml iseddik ble rørt ved 60-65°C i 16 timer. Overskuddet av reagenser ble' fjernet under redusert trykk ved 100°C, og et oljeaktig residum ble -behandlet med et overskudd av 0, 5N saltsyre og 200 ml eter. Et "'• hvitt bunnfall ble fra.filtrert etter 2 timer ved 5-10°C og gjort basisk, hvorved, man fikk det forønskede produkt. Det oljeaktige aminet ble omdannet til et krystallinsk maleat i eter, omkrystallisert fra metanol-eter, noe som ga fargeløse prismer, smp. 123-125°C av 4-(4-fluorbenzylthio)-4-(2-fluorfeny1)-1-metylpiperidinmaleat. a. A mixture of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine from Example 1a (10.5 g), 10 g of p-fluorobenzyl mercaptan, 18 ml of boron trifluoride etherate and 10 ml of glacial acetic acid was stirred at 60- 65°C for 16 hours. The excess of reagents was removed under reduced pressure at 100°C, and an oily residue was treated with an excess of 0.5N hydrochloric acid and 200 ml of ether. A white precipitate was filtered off after 2 hours at 5-10°C and basified to give the desired product. The oily amine was converted to a crystalline maleate in ether, recrystallized from methanol-ether, some which gave colorless prisms, mp 123-125°C of 4-(4-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine maleate.

Analyse:Analysis:

Beregnet for CigH21F2NS • C4H40'4 : 61,45%C, 5,61%H, 3,12%N. Funnet: 61,71.%C, 5,75%H, 3,15%N. Calculated for CigH21F2NS • C4H40'4 : 61.45%C, 5.61%H, 3.12%N. Found: 61.71%C, 5.75%H, 3.15%N.

b. En oppløsning av natrium-metylsulfinylmetid ble fremstilt ved å oppvarme 0,87 g natriumhydrid i 80 ml dimety1-sulfoksyd ved 80°C i. 30 minutter.. Oppløsningen ble så behandlet med 8,9 g av den frie basen 4-(4-fluorbenzylthio)-4-(2-fluorfeny1)-1-metylpiperidin fra eksempel 27a i 20 ml DMSO' i løpet av 2 minutter og røringen ble så fortsatt i 15 minutter ved 80°C før reaksjonen ble stanset med isvann. Blandingen ble ekstrahert tre ganger med CH2C12, og de samlede organiske opp-løsninger ble vasket med vann og tørket og konsentrert til et b. A solution of sodium methylsulfinyl methide was prepared by heating 0.87 g of sodium hydride in 80 ml of dimethyl sulfoxide at 80°C for 30 minutes. The solution was then treated with 8.9 g of the free base 4-( 4-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine from Example 27a in 20 ml of DMSO' over 2 minutes and stirring was then continued for 15 minutes at 80°C before the reaction was quenched with ice water. The mixture was extracted three times with CH 2 Cl 2 , and the combined organic solutions were washed with water and dried and concentrated to a

oljeaktig residum. Rensing av råproduktet ble utført ved kolonnekromatografi (aluminiumoksyd og eter) og en konsentrasjon av de samlede eluater ga en tung olje.som utkrystalliserte seg ved avkjøling. Omkrystallisering fra eter-pentan ga lange nåler, smp. 109-110°C av 3-(4-fluorfeny1)-1,3-dihydro-l<1->metylspiro-[benzo(c)thiofen-1,4'-piperidin]. oily residue. Purification of the crude product was carried out by column chromatography (alumina and ether) and a concentration of the combined eluates gave a heavy oil which crystallized on cooling. Recrystallization from ether-pentane gave long needles, m.p. 109-110°C of 3-(4-fluorophenyl)-1,3-dihydro-1<1->methylspiro-[benzo(c)thiophene-1,4'-piperidine].

Analyse: Beregnet'for C19H2Q<F>NS: 72,81%C, 6,43%H, 4,47%N, 6,38%F. Analysis: Calculated for C19H2Q<F>NS: 72.81%C, 6.43%H, 4.47%N, 6.38%F.

Funnet: 73, 05%C, 6 , 31%H, 4,58%'N, 6,23%F. Found: 73.05%C, 6 , 31%H, 4.58%'N, 6.23%F.

Eksempel 28Example 28

En blanding av 3-(4-fluorfenyl)-1,3-dihydro-l'-mety1-spiro-[benzo (c) thiofen-1, 4 '-piperidin] fra eksempel 27 (3,6 g) .., 2,1 g fenylklorformat i 100 ml CH2C12ble rørt ved romtemperatur i 64 timer.. Oppløsningen ble vasket med 10% vandig NaOH, vann og tørket over magnesiumsulfat. Fordamping under redusert trykk ga et krystallinsk residum, smp. 198-200°C. Omkrystallisering av råproduktet fra aceton-pentan ga granulære krystal- A mixture of 3-(4-fluorophenyl)-1,3-dihydro-1'-methyl-spiro-[benzo(c)thiophene-1,4'-piperidine] from Example 27 (3.6 g) .., 2.1 g of phenylchloroformate in 100 ml of CH2C12 was stirred at room temperature for 64 hours. The solution was washed with 10% aqueous NaOH, water and dried over magnesium sulfate. Evaporation under reduced pressure gave a crystalline residue, m.p. 198-200°C. Recrystallization of the crude product from acetone-pentane gave granular crystals

ler, smp. 200-201°C av 3-( 4-f luorf enyl)-1, 3-dihydro-l.'-f enoksy-" karbonylspiro-[benzo(c)thiofen-1,4'-piperidin]. clay, m.p. 200-201°C of 3-(4-fluorophenyl)-1,3-dihydro-1,'-phenoxy-"carbonylspiro-[benzo(c)thiophene-1,4'-piperidine].

Analyse:Analysis:

Beregnet for C^H^FNO^S: 71,57%C, 5,28%H, 3,34%N.Calculated for C^H^FNO^S: 71.57%C, 5.28%H, 3.34%N.

Funnet:'71,73%C, 5,25%H, 3,20%N. Found: '71.73%C, 5.25%H, 3.20%N.

Eksempel 29Example 29

En blanding av 3-(4-flurofenyl)-1,3-dihydro-l<1->fenoksy-. karbonylspiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 28 (4,3 g), 1,4 g kaliumhydroksyd i 50 ml etylenglykol ble rørt ved 160°C i 30 minutter. Den avkjølte blandingen ble fortynnet med vann og ekstrahert tre ganger med 150 ml porsjoner av eter. Det samlede eterekstraktet ble vasket med vann tre til fire ganger, tørket og konsentrert til et oljeaktig residum av et sekundært amin. Dette ble'omdannet til sitt hydroklorid på van-lig måte ved røring uten oppvarming med saltsyre i flere timer. Omkrystallisering fra metanol-aceton-eter ga krystaller, smp. 259-260°C av 3-(4-fluorfeny1)-1,3-dihydrospiro-[benzo(c)-thiofen-1,4'-piperidin]-hydroklorid. A mixture of 3-(4-fluorophenyl)-1,3-dihydro-1<1->phenoxy-. carbonylspiro-[benzo(c)thiophene-1,4'-piperidine] from Example 28 (4.3 g), 1.4 g of potassium hydroxide in 50 ml of ethylene glycol was stirred at 160°C for 30 minutes. The cooled mixture was diluted with water and extracted three times with 150 ml portions of ether. The combined ether extract was washed with water three to four times, dried and concentrated to an oily residue of a secondary amine. This was converted to its hydrochloride in the usual way by stirring without heating with hydrochloric acid for several hours. Recrystallization from methanol-acetone-ether gave crystals, m.p. 259-260°C of 3-(4-fluorophenyl)-1,3-dihydrospiro-[benzo(c)-thiophene-1,4'-piperidine] hydrochloride.

Analyse:Analysis:

Beregnet for C. 0H-, 0FNS • HC1: 64 , 36%C, 5,70%H, 4,'17%N, 5,65%F.Calculated for C. 0H-, 0FNS • HC1: 64 , 36%C, 5.70%H, 4.'17%N, 5.65%F.

lo lolol lol

Funnet: 64 , 09%C, 5,55%H, 4,28%N, 5,78%F.' Found: 64 , 09%C, 5.55%H, 4.28%N, 5.78%F.'

Eksempel 30Example 30

En blanding av 3-(4-fluorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin] (2,2 g av den frie base fra eksempel 29), 2,2 g y-klor-4-fluorbutyrofenonetylenketal, A mixture of 3-(4-fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine] (2.2 g of the free base from Example 29), 2.2 g y -chloro-4-fluorobutyrophenoneethylene ketal,

1,5 g natriumbikarbonat og 1,5 g kaliumjodid i 25 ml DMF ble rørt ved 80°C i 16 timer. Den avkjølte blandingen ble tilsatt vann, ekstrahert tre ganger med eter og så tørket. Fjerning av oppløsningsmidlet i vakuum i 80°C ga en rødaktig olje som ble renset ved gjennomgang i en kort kolonne av aluminiumoksyd pakket i eter. Eluering med eter ga et rent tertiært amin som ble omdannet til et krystallinsk maleat. Omkrystallisering fra aceton-eter gir fargeløse prismer, smp. 175-177°C av l'-[3-(4-fluorbenzoyl)-propyl]-3-(4-fluorfenyl)-1,3-dihydrospiro-[benzo-(c)thiofen-1,4<1->piperidin]-etylenketalmaleat. 1.5 g sodium bicarbonate and 1.5 g potassium iodide in 25 ml DMF were stirred at 80°C for 16 hours. The cooled mixture was added with water, extracted three times with ether and then dried. Removal of the solvent in vacuo at 80°C gave a reddish oil which was purified by passing through a short column of alumina packed in ether. Elution with ether gave a pure tertiary amine which was converted to a crystalline maleate. Recrystallization from acetone-ether gives colorless prisms, m.p. 175-177°C of 1'-[3-(4-fluorobenzoyl)-propyl]-3-(4-fluorophenyl)-1,3-dihydrospiro-[benzo-(c)thiophene-1,4<1-> piperidine]-ethylene ketal maleate.

Analyse:.Analysis:.

Beregnet for C3QH31F2N02S•C4H404: 65,46%C, 5,64%H, 2,24%N. Funnet: 65,28%C, 5,71%H, 2,21%N. Calculated for C3QH31F2N02S•C4H4O4: 65.46%C, 5.64%H, 2.24%N. Found: 65.28%C, 5.71%H, 2.21%N.

Eksempel 3- 1Example 3- 1

En' oppløsning av 1<1->[3-(p-fluorbenzoyl)propyl]-3-(4-fluorfenyl)-1,3-dihydro-spiro-[benzo(c)thiofen-1,4'-piperidin] etylenketal fra eksempel 30 (2,3 g av den fire base) i 200 ml eter og 10 ml metanol ble mettet med vannfritt hydrogenbromid. Etter henstand ved romtemperatur i 2 timer, ble blandingen, forsiktig nøytralisert med IN ammoniak, og eteroppløsningén ble vasket tre ganger med vann, tørket og konsentrert til et oljeaktig residum. Den frie basen ble omdannet til et krystallinsk maleat i eter og omkrystalliseringen fra aceton-eter gir hvite prismer, smp. 149-150°C av 1'-[3-(4-fluorbenzoyl)propyl]-3-(4-.fluorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-maleat. A' solution of 1<1->[3-(p-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro-[benzo(c)thiophene-1,4'-piperidine] ethylene ketal from Example 30 (2.3 g of the four base) in 200 ml of ether and 10 ml of methanol was saturated with anhydrous hydrogen bromide. After standing at room temperature for 2 hours, the mixture was carefully neutralized with 1N ammonia, and the ether solution was washed three times with water, dried and concentrated to an oily residue. The free base was converted to a crystalline maleate in ether and the recrystallization from acetone-ether gives white prisms, m.p. 149-150°C of 1'-[3-(4-fluorobenzoyl)propyl]-3-(4-.fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4<1->piperidine ]-maleate.

Analyse:Analysis:

Beregnet for C2gH27F2NOS • C4H404: 66 , 31%C, 5,40%H, 2,42%N,' 6,55%F. Funnet: 66,41%C, 5,22%H, 2,36%N, 6,64%F. Eksempel 32 Calculated for C2gH27F2NOS • C4H4O4: 66 , 31%C, 5.40%H, 2.42%N,' 6.55%F. Found: 66.41%C, 5.22%H, 2.36%N, 6.64%F. Example 32

a. 59,7 g 2-klorbenzylmerkaptan fulgt av 55 ml bortrifluorideterat ble tilsatt 25 g 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperidin fra eksempel la i 55 ml eddiksyre. Reaksjonsblandingen ble rørt ved 55-65°C i 20 timer. Overskudd av syre ble fjernet under redusert trykk ved 80-100°C, og- det oljeaktige a. 59.7 g of 2-chlorobenzyl mercaptan followed by 55 ml of boron trifluoride etherate was added to 25 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine from example 1a in 55 ml of acetic acid. The reaction mixture was stirred at 55-65°C for 20 hours. Excess acid was removed under reduced pressure at 80-100°C, and the oily

residumet ble så fordelt mellom 200 ml 2N saltsyre og 200 ml eter. Eteren og to ytterligere 125 ml porsjoner av eter ble avhelt. Oljen og vannblandingen ble fortynnet til 650 ml med vann og lagret ved 0°C over 3 døgn, hvorved man fikk krystaller. Blandingen ble fortynnet og filtrert. Bunnfallet ble the residue was then partitioned between 200 ml of 2N hydrochloric acid and 200 ml of ether. The ether and two additional 125 mL portions of ether were decanted. The oil and water mixture was diluted to 650 ml with water and stored at 0°C for 3 days, whereby crystals were obtained. The mixture was diluted and filtered. The result was

.vasket med vann og eter og så tørket. Det faste stoff ble omkrystallisert fra aceton og eter og man fikk et hvittsmeltende fast stoff, dvs. 122-129°C'i smeltepunkt. En del av dette stoff ble. plassert i vann, gjort basisk med 10% vandig NaOH, ekstrahert over i eter, vasket, tørket og behandlet med hydro-genkloridholdig eter, hvorved man fikk et hvitt pulver. Pulve- .washed with water and ether and then dried. The solid was recrystallized from acetone and ether and a white-melting solid was obtained, i.e. 122-129°C in melting point. Part of this fabric was. placed in water, made basic with 10% aqueous NaOH, extracted into ether, washed, dried and treated with ether containing hydrogen chloride to give a white powder. Pulve-

ret ble omkrystallisert ved aceton-eter og man fikk et hvitt krystallinsk stoff, smp. 173-175°C av 4-(2-klorbenzylthio)-4-(2-fluorfeny1)-1-metylpiperidinhydroklorid. ret was recrystallized from acetone-ether and a white crystalline substance was obtained, m.p. 173-175°C of 4-(2-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine hydrochloride.

Analyse:Analysis:

Beregnet for C<19>H21C1FNS: 59,08%C, 5,74%H,' 3,63%N, 4,92%F.Calculated for C<19>H21C1FNS: 59.08%C, 5.74%H,' 3.63%N, 4.92%F.

Funnet: 58,81%C, 5,63%H, 3,37%N, 5,03%F. Found: 58.81%C, 5.63%H, 3.37%N, 5.03%F.

b. En 0,2 g prøve av natriumhydrid (fremstilt ved åb. A 0.2 g sample of sodium hydride (prepared by

vaske en 50% oljedispersjon) ble oppvarmet til 80°C under røring i 15 ml dimetylsulfoksyd i 30 minutter. Deretter til- wash a 50% oil dispersion) was heated to 80°C with stirring in 15 ml of dimethylsulfoxide for 30 minutes. Then to-

satte man 2,1 g av den frie basen 4-(2-klorbenzylthio)-4-(2-fluorfeny1)-1-metylpiperidin fra eksempel 32a i 10 ml tørr DMSO, 2.1 g of the free base 4-(2-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine from example 32a was added to 10 ml of dry DMSO,

og oljebadet ble så fjernet. Reaksjonen ble hensatt under røring og uten oppvarming i 40 minutter og så helt over i 250 c. m3. is and the oil bath was then removed. The reaction was allowed to stand with stirring and without heating for 40 minutes and then completely poured into 250 c.m3. ice

og 250 ml eter. Lagene ble-ristet og skilt, og den vandigeand 250 ml of ether. The layers were shaken and separated, and the aqueous

delen ekstrahert igjen med 150 ml eter. De samlede eteroppløs-ninger ble vasket med 200 ml porsjoner av vann■og en 10 ml porsjon av en mettet natriumkloridoppløsning, og det hele ble tørket over magnesiumsulfat hvorved man fikk en olje. Oljen ble kromatografert på en kolonne av aluminiumoksyd med eter og man fikk den frie basen som viste ett punkt (Rf 0-, 54, 25% MeOH, the portion extracted again with 150 ml of ether. The combined ether solutions were washed with 200 ml portions of water and a 10 ml portion of a saturated sodium chloride solution, and the whole was dried over magnesium sulfate, whereby an oil was obtained. The oil was chromatographed on an alumina column with ether to give the free base which showed one spot (Rf 0-, 54, 25% MeOH,

CH2C12, silisiumdioksyd) ved hjelp av tynnskiktkromatografi. ' Produktet i eter ble behandlet med et overskudd av maleinsyreholdig eter, vasket med eter og tørket, hvorved man fikk et hvitt pulver,- smp. 17-3-176°C av 3-(2-klorf eny 1) -1, 3-dihydro-l'-■ metylspiro-[benzo(c)thiofen-1,4'-piperidin]-maleat. CH2C12, silicon dioxide) by means of thin-layer chromatography. The product in ether was treated with an excess of maleic ether, washed with ether and dried, whereby a white powder was obtained, m.p. 17-3-176°C of 3-(2-chlorophenyl)-1,3-dihydro-1'-■ methylspiro-[benzo(c)thiophene-1,4'-piperidine]-maleate.

En liten del av saltet ble omkrystallisert to gangerA small portion of the salt was recrystallized twice

fra aceton og man fikk krystaller som smelter ved 178-178,5°C. from acetone and crystals were obtained which melt at 178-178.5°C.

Analyse:Analysis:

Beregnet for C19H20C1NS•C4H404: 61,95%C, 5,43%H, 3,14%N, 7,95%C1. Funnet: 62,03%C, 5,46%H, 3,10%N, 7,94%C1. Eksempel 33 Calculated for C19H20C1NS•C4H4O4: 61.95%C, 5.43%H, 3.14%N, 7.95%C1. Found: 62.03%C, 5.46%H, 3.10%N, 7.94%C1. Example 33

a. En blanding av 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperidin fra eksempel la (15,8 g), 12 ml 2-fluorbenzyl-merkaptan og 20 ml bortrifluorideterat i 15 ml iseddik ble rørt ved 65-70°C i 16 timer. Overskuddet av reagenser ble fjernet under redusert trykk, og residumet behandlet med 300 ml 0,5N HC1 og 100 ml eter. Etter henstand ved 5-10<Q>C i 30 minutter, frafiltrerte man det krystallinske bunnfallet, dette ble luft-.tørket og gjort basisk med 10%- vandig NH4OH. Det frigjorte amin ble tatt opp i eter, tørket og konsentrert til en gulaktig olje som så ble omdannet til sitt maleat i eter, og en omkrystallisering av dette saltet fra metanol og. eter gir fargeløse prismer, smp. 153-154°C av 4-(2-fluorbenzylthio)-4-(2-fluor-fenyl) -1-metylpiperidinmaleat. a. A mixture of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine from Example 1a (15.8 g), 12 ml of 2-fluorobenzyl mercaptan and 20 ml of boron trifluoride etherate in 15 ml of glacial acetic acid was stirred at 65- 70°C for 16 hours. The excess reagents were removed under reduced pressure and the residue treated with 300 ml of 0.5N HCl and 100 ml of ether. After standing at 5-10<Q>C for 30 minutes, the crystalline precipitate was filtered off, this was air-dried and made basic with 10% aqueous NH 4 OH. The liberated amine was taken up in ether, dried and concentrated to a yellowish oil which was then converted to its maleate in ether, and a recrystallization of this salt from methanol and. ether gives colorless prisms, m.p. 153-154°C of 4-(2-fluorobenzylthio)-4-(2-fluoro-phenyl)-1-methylpiperidine maleate.

Analyse:Analysis:

Beregnet for c1gH2iF2NS" C4H4°4: 61,45%C, 5,61.%H, 3,12%N.Calculated for c1gH2iF2NS" C4H4°4: 61.45%C, 5.61%H, 3.12%N.

Funnet: 61,28.%C, 5,57%H, 2,98%N. Found: 61.28%C, 5.57%H, 2.98%N.

b. En oppløsning av natrium-metylsulfinylmethid ble fremstilt ved å oppvarme 1,2 g natriumhydrid i 100 ml DMSO ved 80°C i 30 minutter. Blandingen ble avkjølt til romtemperatur og tilsatt 12 g av den frie basen 4-(2-fluorbenzylthio)- 4-(2-f luorf enyl.)-1-me.ty lpiperidin ■ i 40 ml DMSO i løpet av 5 minutter. Blandingen ble så rørt ved 70-80°C i ytterligere 30 minutter. Blandingen ble fortynnet med isvann og ekstrahert tre ganger med eter. De samlede eteroppløsninger ble vasket fire ganger med vann, tørket og konsentrert.til en tykk olje. Kromatografi på aluminiumoksyd og eter som elueringsmiddel fjerner en mindre mengde urenheter, og det rensede amin ble omdannet til et krystallinsk hydrobromid i eter. Omkrystallisering fra metanol-eter gir fargeløse krystaller, smp. 263-265°C (dekomponering) av 3-(2-fluorfenyl)-1,3-dihydro-l'-metylspiro-[benzo(c)thiofen-1,4<1->piperidin]-hydrobromid. b. A solution of sodium methylsulfinyl methide was prepared by heating 1.2 g of sodium hydride in 100 ml of DMSO at 80°C for 30 minutes. The mixture was cooled to room temperature and 12 g of the free base 4-(2-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine in 40 ml of DMSO were added over 5 minutes. The mixture was then stirred at 70-80°C for a further 30 minutes. The mixture was diluted with ice water and extracted three times with ether. The combined ether solutions were washed four times with water, dried and concentrated to a thick oil. Chromatography on alumina and ether as eluent removes a minor amount of impurities, and the purified amine was converted to a crystalline hydrobromide in ether. Recrystallization from methanol-ether gives colorless crystals, m.p. 263-265°C (decomposition) of 3-(2-fluorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c)thiophene-1,4<1->piperidine]-hydrobromide.

Analyse:Analysis:

Beregnet for C19H2QFNS-HBr: 57,86%C, 5,37%H, 3,55%N, 4,82%F. Funnet: 57,67%C, 5,47%H, 3,58%N, 4,80%F. Calculated for C19H2QFNS-HBr: 57.86%C, 5.37%H, 3.55%N, 4.82%F. Found: 57.67%C, 5.47%H, 3.58%N, 4.80%F.

Eksempel 34Example 34

En blanding av de frie aminer 3-(2-fluorfenyl)-1,3-dihydro-1'-metylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 33 (5,3 g), 3,9 g fenylklorformat i 100 ml vannfri CH2Cl2ble rørt ved romtemperatur i 4 timer. Reaksjonsblandingen ble så vasket med 10% vandig natriumhydrid og tørket over magnesiumsulfat i 2 timer. A mixture of the free amines 3-(2-fluorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c)thiophene-1,4<1->piperidine] from example 33 (5.3 g) , 3.9 g of phenylchloroformate in 100 ml of anhydrous CH2Cl2 was stirred at room temperature for 4 hours. The reaction mixture was then washed with 10% aqueous sodium hydride and dried over magnesium sulfate for 2 hours.

Fjerning av oppløsningsmidlet under redusert trykk fører til en tykk olje som ble renset ved gjennomgang i en kort silisiumdioksyd gelkolonne pakket i CE^C^. Eluering med stort overskudd av.Cf^C^ ga etter konsentrasjon en fargeløs olje som stivnet ved henstand, hvorved man fikk 3-(2-fluor-fenyl) -1,3-dihydro-l'-fenoksykarbonylspiro-[benzo(c)thiofen-i, 4<1->piperidin], smp. 122-123°C. Removal of the solvent under reduced pressure left a thick oil which was purified by passage through a short silica gel column packed in CE^C^. Elution with a large excess of .Cf^C^ gave, after concentration, a colorless oil which solidified on standing, giving 3-(2-fluoro-phenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-[benzo(c) thiophene-i, 4<1->piperidine], m.p. 122-123°C.

Analyse:Analysis:

Beregnet for C25H22FN02S: 71'57%C'5,28%H, 3,34%N.Calculated for C25H22FN02S: 71'57%C'5.28%H, 3.34%N.

Funnet:' 71,49%C, 5,23%H, 3,27%N. Found:' 71.49%C, 5.23%H, 3.27%N.

Eksempel 35Example 35

En blanding av 3-(2-fluorfenyl)-1,3-dihydro-l<1->fenoksy-karbonylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 34 (5,6 g), 18 g kaliumhydroksyd i 100 ml etylenglykol ble rørt ved 170°C i 30 minutter. Blandingen ble helt over i vann, og ekstrahert tre ganger med eter. Eteroppløsningen ble vasket med vann, tørket og konsentrert i vakuum hvorved man fikk en viskøs olje av det frie aminet. Et krystallinsk maleat ble fremstilt og omkrystallisert fra metanol-aceton-eter, hvorved man fikk et hvitt pulver av 3-(2-fluorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-maleat. A mixture of 3-(2-fluorophenyl)-1,3-dihydro-1<1->phenoxy-carbonylspiro-[benzo(c)thiophene-1,4<1->piperidine] from Example 34 (5.6 g ), 18 g of potassium hydroxide in 100 ml of ethylene glycol was stirred at 170°C for 30 minutes. The mixture was poured into water and extracted three times with ether. The ether solution was washed with water, dried and concentrated in vacuo to give a viscous oil of the free amine. A crystalline maleate was prepared and recrystallized from methanol-acetone-ether to give a white powder of 3-(2-fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine]- maleate.

Analyse:Analysis:

Beregnet for C gH gFNS'C^O^: 63, 59%C, 5,34%H, 3,37%N, 4,57%F. Funnet: 63,55%C, 5,33%H, 3,10%N, 4,52%F. Calculated for C gH gFNS'C^O^: 63, 59%C, 5.34%H, 3.37%N, 4.57%F. Found: 63.55%C, 5.33%H, 3.10%N, 4.52%F.

Eksempel 36Example 36

En blanding av 3-(2-fluorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 35 (2,2 g), 2,2 g y-klor-4-fluorbutyrofenonetylenketalforbindelsen, 1,5 g kaliumjodid og 1,5 g natriumbikarbonat i 25 ml DMF ble rørt ved 70-75 °C i 16 timer. Den avkjølte blanding ble fortynnet med vann og blandingen ekstrahert tre ganger med eter. Eteroppløsningen ble etter vasking med vann og tørking, konsentrert i vakuum til et oljeaktig residum som ble renset gjennom en kort kolonne av aluminiumoksyd. Eluering med eter gir en fargeløs olje som ble omdannet til'et krystallinsk maleat, smp. 150-151°C av l'-[3-(4-fluorbenzoyl)propyl]-3-(2-fluorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-etylenketalmaleat. A mixture of 3-(2-fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine] from Example 35 (2.2 g), 2.2 g γ-chloro-4 The -fluorobutyrophenoneethylene ketal compound, 1.5 g of potassium iodide and 1.5 g of sodium bicarbonate in 25 ml of DMF were stirred at 70-75 °C for 16 hours. The cooled mixture was diluted with water and the mixture extracted three times with ether. The ether solution was, after washing with water and drying, concentrated in vacuo to an oily residue which was purified through a short column of alumina. Elution with ether gave a colorless oil which was converted to a crystalline maleate, m.p. 150-151°C of 1'-[3-(4-fluorobenzoyl)propyl]-3-(2-fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine]-ethylene ketal maleate .

Analyse:Analysis:

Beregnet for<c>30<H>30F2NO2S'C4H4°4: 65'46%C'5 , 64%H, 2,24%N. Funnet: 65,46%C, 5,37%H, 2,12%N. Calculated for<c>30<H>30F2NO2S'C4H4°4: 65'46%C'5 , 64%H, 2.24%N. Found: 65.46%C, 5.37%H, 2.12%N.

Eksempel 37Example 37

En oppløsning av 1'-[3-(4-fluorbenzoyl)propyl]-3-(2-fluorfeny1)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-etylenketal fra eksempel 36 (2,0 g) i 20 ml etanol og 20 ml 3N saltsyre ble oppvarmet på et dampbad i 30 minutter. Den av-kjølte oppløsning ble gjort basisk med 40% vandig natriumhydroksyd og ekstrahert tre ganger med- eter. Den samlede eteropp-løsning ble vasket med vann, tørket og,behandlet med et overskudd av maleinsyreholdig eter. Man fikk et krystallinsk maleat som ble omkrystallisert fra aceton-eter, og man fikk hvite prismer, smp. 137-138, 5°C av 11-[3-(4-fluorbenzoyl)propyl]- - 3-(2-fluorfeny1)-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin ]-maleat. A solution of 1'-[3-(4-fluorobenzoyl)propyl]-3-(2-fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine]-ethylene ketal from Example 36 (2.0 g) in 20 ml of ethanol and 20 ml of 3N hydrochloric acid was heated on a steam bath for 30 minutes. The cooled solution was basified with 40% aqueous sodium hydroxide and extracted three times with ether. The combined ether solution was washed with water, dried and treated with an excess of maleic ether. A crystalline maleate was obtained which was recrystallized from acetone-ether, and white prisms were obtained, m.p. 137-138, 5°C of 11-[3-(4-fluorobenzoyl)propyl]- - 3-(2-fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4<1-> piperidine ]-maleate.

Analyse:Analysis:

Beregnet for C2gH27F2NO•C4H404: 66, 31%C, 5,40%H, 2,42%N, 6,55%F. Funnet: 66,18%C, 5,34%H, 2,42%N, 6,49%F. Calculated for C2gH27F2NO•C4H4O4: 66, 31%C, 5.40%H, 2.42%N, 6.55%F. Found: 66.18%C, 5.34%H, 2.42%N, 6.49%F.

Eksempel 38Example 38

En 4,5 g prøve av fenylklorformat i 150 ml diklormetan ble. rørt ved 25°C mens man raskt tilsatte 7,5- g 1, 3-di-hydro-1'-mety1-3-(2-mety1fenyl)spiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 23 i 75 ml diklormetan. Blandingen ble rørt 24 timer ved 25°C og så tilsatt 225 ml 10% vandig NaOH-oppløsning. Det organiske laget ble utskilt og vasket med vann, tørket over magnesiumsulfat, filtrert og fordampet til en olje. Denne ble kolonnekromatografert på silisiumdioksydgel/CH2Cl2-kolonne hvor man brukte CH2C12som elueringsmiddel. Det isolerte produktet er en blekt gul olje av 1,3-dihydro-3-(2-metylfeny1)-1<1->fenoksy-karbonylspiro- [benzo(c)thiofen-1,4'-piperidin]. A 4.5 g sample of phenyl chloroformate in 150 ml of dichloromethane was. stirred at 25°C while rapidly adding 7.5 g of 1,3-dihydro-1'-methyl-3-(2-methylphenyl)spiro-[benzo(c)thiophene-1,4'-piperidine] from Example 23 in 75 ml of dichloromethane. The mixture was stirred for 24 hours at 25°C and then 225 ml of 10% aqueous NaOH solution was added. The organic layer was separated and washed with water, dried over magnesium sulfate, filtered and evaporated to an oil. This was column chromatographed on a silica gel/CH2Cl2 column where CH2C12 was used as eluent. The isolated product is a pale yellow oil of 1,3-dihydro-3-(2-methylphenyl)-1<1->phenoxy-carbonylspiro-[benzo(c)thiophene-1,4'-piperidine].

Analyse:Analysis:

Beregnet for C26<H>25N02S: 75,15%C, 6,06%H.Calculated for C26<H>25N02S: 75.15%C, 6.06%H.

Funnet: 74,90%C, 6,05%H.Found: 74.90%C, 6.05%H.

Eksempel 39Example 39

En oppløsning av 16 g kaliumhydroksyd oppløst i 100 ml etylenglykol ble tilsatt 6,0 g 1,3-dihydro-3-(2-metylfenyl)-1<1->fenoksykarbonylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 38. Den resulterende oppløsning ble rørt og holdt ved 16'0°C i. en time. Den ble så helt over i 300 ml isvann og ekstrahert med eter. Eterfraksjonene ble samlet, vasket med vann og tørket over magnesiumsulfat, filtrert og fordampet til et residum som ble omdannet til et hvitt, granulært maleatsalt, 1,3-dihydro-3-(2-metylfenyl)spiro-[benzo(c)thiofen-1,4<1->piperidin] -maleat , som ble omkrystallisert fra metanol-eter og har da et smeltepunkt på 178-179°C. A solution of 16 g of potassium hydroxide dissolved in 100 ml of ethylene glycol was added to 6.0 g of 1,3-dihydro-3-(2-methylphenyl)-1<1->phenoxycarbonylspiro-[benzo(c)thiophene-1,4<1 ->piperidine] from Example 38. The resulting solution was stirred and held at 16-0°C for one hour. It was then poured into 300 ml of ice water and extracted with ether. The ether fractions were combined, washed with water and dried over magnesium sulfate, filtered and evaporated to a residue which was converted to a white granular maleate salt, 1,3-dihydro-3-(2-methylphenyl)spiro-[benzo(c)thiophene- 1,4<1->piperidine] maleate, which was recrystallized from methanol-ether and then has a melting point of 178-179°C.

Analyse:Analysis:

Beregnet for CigH21NS•C4H404: 67,13%C, 6,12%H, 3,40%N. Funnet: 67,10%C, 5,96%H., 3,14%N. Calculated for CigH21NS•C4H4O4: 67.13%C, 6.12%H, 3.40%N. Found: 67.10%C, 5.96%H., 3.14%N.

Eksempel 40Example 40

En blanding av 6,0 g 1,3-dihydro-3-(4-metylfenyl)-1'-fenoksykarbonylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 13, 16,0 g kaliumhydroksyd og 100 ml etylenglykol ble rørt og holdt på 160°C i en-time. Blandingen ble. så tilsatt isvann og 'ekstrahert med eter. Eterekstraktene ble slått sammen, vasket med vann, tørket, over magnesiumsulfat og fordampet til én olje. Denne oljen ble omdannet til 1,3-dihydro-3-(4-mety1fenyl)spiro-[benzo(c)thiofen-1,4'-piperidin]-maleat, smp. 214-215°C. A mixture of 6.0 g of 1,3-dihydro-3-(4-methylphenyl)-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4<1->piperidine] from Example 13, 16.0 g potassium hydroxide and 100 ml of ethylene glycol were stirred and kept at 160°C for one hour. The mixture was then added ice water and 'extracted with ether. The ether extracts were combined, washed with water, dried over magnesium sulfate and evaporated to an oil. This oil was converted to 1,3-dihydro-3-(4-methylphenyl)spiro-[benzo(c)thiophene-1,4'-piperidine]-maleate, m.p. 214-215°C.

Analyse: Beregnet for C19H21NS ' C4H4°4 : 67,13%C, 6,12%'H, 3,40%N. Funnet: 67,05%C, 6,20%H, 3,21%N. Eksempel 41 Analysis: Calculated for C19H21NS 'C4H4°4 : 67.13%C, 6.12%'H, 3.40%N. Found: 67.05%C, 6.20%H, 3.21%N. Example 41

a. 25 g 4-(2-fluorfenyl)-4-hydroksyl-l-metylpiperidin fra eksempel la ble tilsatt 50 g m-metylbenzylmerkaptan. Blandingen ble så tilsatt 68. ml bortrif luorid-eterat. Blandingen ble så rørt ved 65-70°C i 3 døgn. Overskuddet av reagens ble så fjernet under vakuum ved • 60-100°C. Blandingen ble så helt over i 360 ml 0,5N saltsyre og 300 ml eter. Man fikkutfelt en olje som ble avhelt eter og vann. Oljen ble tilsatt 250 ml 0,5N saltsyre og 200 ml eter. Oljen ble igjen utskilt fra disse oppløsninger og tilsatt 150 ml vann og 20 ml av en 10% vandig ■ natriumhydroksydoppløsning. Suspensjonen ble ytterligere for- a. 25 g of 4-(2-fluorophenyl)-4-hydroxyl-1-methylpiperidine from example la was added to 50 g of m-methylbenzylmercaptan. To the mixture was then added 68 ml of boron trifluoride etherate. The mixture was then stirred at 65-70°C for 3 days. The excess reagent was then removed under vacuum at • 60-100°C. The mixture was then poured into 360 ml of 0.5N hydrochloric acid and 300 ml of ether. An oil was precipitated which was washed off with ether and water. The oil was added to 250 ml of 0.5N hydrochloric acid and 200 ml of ether. The oil was again separated from these solutions and 150 ml of water and 20 ml of a 10% aqueous ■ sodium hydroxide solution were added. The suspension was further

tynnet med 200 ml vann og ekstrahert med to 200 ml porsjoner og en 100 ml porsjon med eter. De samlede eterekstrakter ble tilsatt en oppløsning av 12,5 ml 48% vandig hydrogenbromid i 300 ml vann, og man fikk et hvitt salt. Blandingen ble hensatt i 16 timer og eteren ble så avhelt. Den vandige blandingen ble igjen vasket ved tilsetning og avhelling av 200 ml eter. Saltet ble så frafiltrert, vasket med vann og eter og så tørket til et hvitt"pulver, smp. 143-145°C av 4-(2-fluor-fenyl)-4-(3-metylbenzylthio)-1-metylpiperidinhydrobromid. En tre ganger omkrystallisert prøve (aceton-eter) smelter ved 145-146°C. diluted with 200 ml of water and extracted with two 200 ml portions and one 100 ml portion of ether. A solution of 12.5 ml of 48% aqueous hydrogen bromide in 300 ml of water was added to the combined ether extracts, and a white salt was obtained. The mixture was allowed to stand for 16 hours and the ether was then poured off. The aqueous mixture was again washed by adding and decanting 200 ml of ether. The salt was then filtered off, washed with water and ether and then dried to a white powder, m.p. 143-145°C of 4-(2-fluoro-phenyl)-4-(3-methylbenzylthio)-1-methylpiperidine hydrobromide. three times recrystallized sample (acetone-ether) melts at 145-146°C.

Analyse:Analysis:

Beregnet for C H24FNS-HBr: 58, 54%C, -6,14%H, 3,4%N. • Funnet: 58,45%C, 6,16%H, 3,16%N. Calculated for C H24FNS-HBr: 58, 54%C, -6.14%H, 3.4%N. • Found: 58.45%C, 6.16%H, 3.16%N.

b. En 3,43 g porsjon av en 50% natriumhydriddispersjon ble vasket med heksan under tørr nitrogen og så oppvarmet med 100 ml av siltørket dimetylsulfoksyd ved 80-85°C i 40 minutter. I løpet av ett minutt tilsatte man så 18,48 g av den frie basen av 4-(2-fluorfenyl)-4-(3-metylbenzylthio)-1-metylpiperidin fra eksempel 41a i 70 ml tørr DMSO. Den røde blandingen ble rørt, avkjølt til romtemperatur i løpet av en time og så helt over i 500 cm 3 isvann. Den vandige blandingen ble ekstrahert med tre 200 ml porsjoner av diklormetan. De samlede diklormetanekstrakter ble vasket med fire 200 ml porsjoner av vann • og en 100 ml porsjon av mettet vandig natriumkloridoppløsning, og deretter tørket over magnesiumsulfat hvorved man fikk en olje. Denne ble oppløst i eter, filtrert, fordampet og kromatografert på 400 ml aluminiumoksyd med eter, hvorved man fikk en olje som ble oppløst i eter og behandlet med eterholdig hydrogenbromid og dette ga et salt. Saltet ble vasket med eter og omkrystallisert fra metanol-aceton-eter til et hvitt, krystallinsk pulver, smp. 258-260°C av 1,3-dihydro-l'-metyl-3-(3-mety1fenyl)spiro-[benzo(c)thiofen-1,4'-piperidin]-hydrobromid. b. A 3.43 g portion of a 50% sodium hydride dispersion was washed with hexane under dry nitrogen and then heated with 100 ml of screen-dried dimethyl sulfoxide at 80-85°C for 40 minutes. In the course of one minute, 18.48 g of the free base of 4-(2-fluorophenyl)-4-(3-methylbenzylthio)-1-methylpiperidine from Example 41a in 70 ml of dry DMSO were then added. The red mixture was stirred, cooled to room temperature over one hour and then poured into 500 cm 3 of ice water. The aqueous mixture was extracted with three 200 mL portions of dichloromethane. The combined dichloromethane extracts were washed with four 200 ml portions of water • and one 100 ml portion of saturated aqueous sodium chloride solution, and then dried over magnesium sulfate to give an oil. This was dissolved in ether, filtered, evaporated and chromatographed on 400 ml of aluminum oxide with ether, whereby an oil was obtained which was dissolved in ether and treated with ethereal hydrogen bromide and this gave a salt. The salt was washed with ether and recrystallized from methanol-acetone-ether to a white, crystalline powder, m.p. 258-260°C of 1,3-dihydro-1'-methyl-3-(3-methylphenyl)spiro-[benzo(c)thiophene-1,4'-piperidine] hydrobromide.

Analyse:Analysis:

Beregnet for C^H^NS «HBr:61,54%C, 6,20%H, 3,59%N.Calculated for C^H^NS «HBr: 61.54%C, 6.20%H, 3.59%N.

Funnet: 61,27%C, 6,24%H, 3,45%N. Found: 61.27%C, 6.24%H, 3.45%N.

Eksempel 4 2Example 4 2

En oppløsning av 0,70 g av aminet 1,3-dihydro-3-(2-metylfenyl)spiro[benzo(c)thiofen-1,4'-piperidin] fra eksempel 39, 0,76 g y~klor-p-fluorbutyrofenonetylenketal, 0,38 g natriumbikarbonat, 0,38 g Kl og 10 ml vannfri DMF ble rørt og holdt på 70-80°C i 24 timer. Reaksjonsblandingen ble opp-arbeidet ved overhelling i vann og ekstraksjon'med eter. Eterfraksjonene ble slått sammen, vasket med vann og tørket over magnesiumsulfat. Oppløsningen ble filtrert, fordampet og den resulterende oljen kolonnekromatografert på en aluminiumoksyd/eter-kolonne (eluering med eter). Det isolerte produktet ble omdannet til maleatsalt av 11-[3-(4-fluorbenzoyl)-propyl]-l,3-dihydro-3-(2-metylfenylspiro-[benzo(c)thiofen-1,4'-piperidinj-etylenketalmaleat, smp. 157-159°C. A solution of 0.70 g of the amine 1,3-dihydro-3-(2-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine] from Example 39, 0.76 g of y~chloro-p- fluorobutyrophenoneethylene ketal, 0.38 g sodium bicarbonate, 0.38 g Kl and 10 ml anhydrous DMF were stirred and kept at 70-80°C for 24 hours. The reaction mixture was worked up by pouring into water and extraction with ether. The ether fractions were combined, washed with water and dried over magnesium sulfate. The solution was filtered, evaporated and the resulting oil column chromatographed on an alumina/ether column (elution with ether). The isolated product was converted to the maleate salt of 11-[3-(4-fluorobenzoyl)-propyl]-1,3-dihydro-3-(2-methylphenylspiro-[benzo(c)thiophene-1,4'-piperidinj-ethylene ketal maleate , mp 157-159°C.

Analyse:Analysis:

Beregnet for C31H34FN02S•C4H404: 67,83%C, .6,81%H, 2,26%N. Funnet: 67,78%C, 6,02%H, 2,24%N. Eksempel 43 Calculated for C31H34FN02S•C4H4O4: 67.83%C, .6.81%H, 2.26%N. Found: 67.78%C, 6.02%H, 2.24%N. Example 43

3,83 g. f eny lklorf ormat i 850 ml diklormetan ble tilsatt en oppløsning av 6,73 g av den frie basen 3-(2-klorfeny1)-1,3-dihydro-l'-metylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 32 i 75 ml diklormetan i løpet av 2 minutter. Blandingen ble rørt ved romtemperatur i 64 timer, så fortynnet med 200 ml diklormetan og vasket med to 300 ml porsjoner av 5% vandig natriumhydroksydoppløsning, to 200 ml porsjoner vann og en 75 ml porsjon av natriumkloridoppløsning. Oppløsningen ble tørket over magnesiumsulfat og fordampet til en olje. Denne ble kromatografert på en silisiumdioksydgelkolonne med diklormetan, og man fikk en olje av 3-(2-klorfeny1)-1,3-dihydro-l'-fenoksykarbonylspiro-[benzo(c)thiofen-1,4<1->piperidin]. Analyse: 3.83 g of phenyl chloroformate in 850 ml of dichloromethane was added to a solution of 6.73 g of the free base 3-(2-chlorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c) thiophene-1,4<1->piperidine] from Example 32 in 75 ml of dichloromethane over 2 minutes. The mixture was stirred at room temperature for 64 hours, then diluted with 200 ml of dichloromethane and washed with two 300 ml portions of 5% aqueous sodium hydroxide solution, two 200 ml portions of water and one 75 ml portion of sodium chloride solution. The solution was dried over magnesium sulfate and evaporated to an oil. This was chromatographed on a silica gel column with dichloromethane, and an oil of 3-(2-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4<1->piperidine] was obtained . Analysis:

Beregnet for C25H22C1N02S: 68,88%C, 5,09%H, '3,21%N.Calculated for C25H22C1N02S: 68.88%C, 5.09%H, '3.21%N.

Funnet: 69,36%C, 4,94%H, 3,33%N. Eksempel 44. Found: 69.36%C, 4.94%H, 3.33%N. Example 44.

1,81 g fenylklorformat i 40. ml diklormetan ble tilsatt en oppløsning av 2,98 g av den frie basen 1,3-dihydro-1<1->metyl-3-(3-mety1fenyl)spiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 41 i 35 ml diklormetan i løpet av 5 minutter. Blandingen ble rørt ved romtemperatur i 21 timer. Den ble så 1.81 g of phenylchloroformate in 40 ml of dichloromethane was added to a solution of 2.98 g of the free base 1,3-dihydro-1<1->methyl-3-(3-methylphenyl)spiro-[benzo(c) thiophene-1,4<1->piperidine] from Example 41 in 35 ml of dichloromethane during 5 minutes. The mixture was stirred at room temperature for 21 hours. It became so

fortynnet med 100 ml diklormetan, vasket med to 150 ml porsjoner av en 5% vandig natriumhydroksydoppløsning, to 100 ml porsjoner med vann og en 50 ml. porsjon med natriumkloridoppløs-ning. Den ble så tørket over magnesiumsulfat og man fikk en olje. Denne ble kromatografert på en silisiumdioksydgelkolonne med diklormetan som elueringsmiddel, noe som ga 1,3-dihydro-3-(3-metylfenyl)-11-fenoksykarbonylspiro-[benzo(c)thiofen-1,41 - piperidin], smp. 154-157°C. En del ble omkrystallisert fra toluen-heksan, og smeltepunktet var da 157-160°C. diluted with 100 ml of dichloromethane, washed with two 150 ml portions of a 5% aqueous sodium hydroxide solution, two 100 ml portions of water and one 50 ml. portion with sodium chloride solution. It was then dried over magnesium sulfate and an oil was obtained. This was chromatographed on a silica gel column with dichloromethane as eluent, which gave 1,3-dihydro-3-(3-methylphenyl)-11-phenoxycarbonylspiro-[benzo(c)thiophene-1,41-piperidine], m.p. 154-157°C. A part was recrystallized from toluene-hexane, and the melting point was then 157-160°C.

Analyse:Analysis:

Beregnet for C^H^NC^S: 75,16%C, 6,07%H, 3,37%N.Calculated for C^H^NC^S: 75.16%C, 6.07%H, 3.37%N.

Funnet: 75,28%C, 6,12%H, 3,17%N. Found: 75.28%C, 6.12%H, 3.17%N.

Eksempel 45Example 45

6,19 g 3-(2-klorfenyl)-1,3-dihydro-l'-fenoksykarbonyl-spiro- [benzo(c)thiofen-1,4'-piperidin] fra eksempel 43 i 95 ml etylenglykol ved 150°C ble tilsatt 15,1 g 85% kaliumhydroksydpellets. Blandingen ble rørt ved 160-165°C k 40 minutter, så 6.19 g of 3-(2-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonyl-spiro-[benzo(c)thiophene-1,4'-piperidine] from Example 43 in 95 ml of ethylene glycol at 150°C 15.1 g of 85% potassium hydroxide pellets were added. The mixture was stirred at 160-165°C for 40 minutes, so

avkjølt'til romtemperatur og helt over i 250 ml vann. Blandingen ble fortynnet til 500 ml med vann og ekstrahert med tre 150 ml porsjoner av vann og en 40 ml porsjon av en mettet natriumkloridoppløsning og så tørket over magnesiumsulfat, hvorved man fikk en olje. Denne ble oppløst i eter, filtrert og behandlet med maleinsyreholdig eter. Råsaltet ble vasket med eter og omkrystallisert fra metanol-aceton-eter,• hvorved man fikk et hvitt salt av 3-(2-klorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-maleat, smp. 172-173°C. Analyse: Beregnet for C18H18C1NS: 61,18%C, 5,14%H,'3,24%N, 8,21%C1. Funnet: 61,47%C, 5,22%H, 3,18%N, 7,85%C1. Eksempel 46 cooled to room temperature and poured into 250 ml of water. The mixture was diluted to 500 ml with water and extracted with three 150 ml portions of water and one 40 ml portion of a saturated sodium chloride solution and then dried over magnesium sulfate to give an oil. This was dissolved in ether, filtered and treated with ether containing maleic acid. The crude salt was washed with ether and recrystallized from methanol-acetone-ether,• whereby a white salt of 3-(2-chlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4<1-> piperidine] maleate, m.p. 172-173°C. Analysis: Calculated for C18H18C1NS: 61.18%C, 5.14%H,'3.24%N, 8.21%C1. Found: 61.47%C, 5.22%H, 3.18%N, 7.85%C1. Example 46

2,48 g av den frie basen 3-(2-klorfenyl)-1,3-dihydro-spiro- [benzo ( c) thiof en-1 , 4 1 -piperidin ] fra eksempel 45 i 28 ml siltørket dimetylformamid og 2,78 g y-klor-p-fluorfenylbutyro-fenonetylenketal ble tilsatt 2,02 g natriumbikarbonat og 2,02 g kaliumjodid..Blandingen ble så holdt på 85-90°C i 17 timer. 2.48 g of the free base 3-(2-chlorophenyl)-1,3-dihydro-spiro-[benzo(c)thiophene-1,41-piperidine] from Example 45 in 28 ml of sieve-dried dimethylformamide and 2, 78 g of γ-chloro-p-fluorophenylbutyro-phenoneethylene ketal was added to 2.02 g of sodium bicarbonate and 2.02 g of potassium iodide. The mixture was then kept at 85-90°C for 17 hours.

Blandingen ble fortynnet med 90 ml kloroform og filtrert gjennom papir. Oppløsningen ble fordampet, og oljen delt mellom 140 ml diklormetan og 75 ml vann. Diklormétanen ble vasket med 75 ml vann og en 25 ml porsjon av mettet natriumkloridoppløs-- ning og så tørket over magnesiumsulfat. Oljen ble kromatografert på aluminiumoksyd med eter og så behandletmed eterholdig oksalsyre til et salt. Dette ble vasket med eter og omkrystallisert fra metanol-aceton-eter (smp. 200-201°C), hvorved man fikk et hvitt fast stoff av 3-(2-klorfeny1)-1'-[3-(4-fluor-benzoyl) propyl]-l,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin ] -etylenketaloksalat , smp. 200-201°C. The mixture was diluted with 90 ml of chloroform and filtered through paper. The solution was evaporated and the oil partitioned between 140 ml of dichloromethane and 75 ml of water. The dichloromethane was washed with 75 ml of water and a 25 ml portion of saturated sodium chloride solution and then dried over magnesium sulfate. The oil was chromatographed on alumina with ether and then treated with ethereal oxalic acid to form a salt. This was washed with ether and recrystallized from methanol-acetone-ether (m.p. 200-201°C), whereby a white solid of 3-(2-chlorophenyl)-1'-[3-(4-fluoro- benzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine]-ethylene ketaloxalate, m.p. 200-201°C.

• Analyse:• Analysis:

Beregnet for C30<H>31ClFNO2S-C2H2O4:. 62, 59%C, 5,42%H, 2,28%N. Funnet: 62,53%C, 5,44%H, 2,26%N. Eksempel 47 Calculated for C30<H>31ClFNO2S-C2H2O4:. 62, 59%C, 5.42%H, 2.28%N. Found: 62.53%C, 5.44%H, 2.26%N. Example 47

a. 14,45 g 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperidin fra eksempel la' ble tilsatt 39, 45 g 2,4-diklorbenzylmerkap-tan etterfulgt av 40 ml bortrifluorideterat. Blandingen ble rørt ved 80-85°C i 4 døgn. Overskuddet av reagens ble fjernet under vakuum ved 110°C, og den gjenværende oljen helt over i 200 ml 0,5N saltsyre og.200 ml eter. Blandingen ble hensatt i 18 timer, eteren avhelt og to ytterligere 200 ml porsjoner eter ble tilsatt og avhelt. Bunnfallet ble frafiltrert, vasket med 75 ml vann og tre 125 ml porsjoner av eter og så tørket til et tilsynelatende blandet salt. En del av saltet ble gjort basisk i vandig ammoniumhydroksyd, ekstrahert med eter, vasket med vann og natriumkloridoppløsning og så tørket over magnesiumsulfat. Eteroppløsningen ble behandlet med eterholdig hydrogenbromid til et salt. Dette ble vasket med eter og tørket til. et hvitt pulver av 4-( 2 , 4-diklprbenzy lthio)-4- ( 2-f luorf enyl) 1-metylpiperidin-hydrobromid, smp. 208,5-210°C. Analyse:' Beregnet for Cig<H>20Cl2FNS-HBr: 49,05%C, 4,55%H, 3,01%N. Funnet: 48,87%C, 4,52%H, 2,96%N. a. 14.45 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine from Example 1a' was added to 39.45 g of 2,4-dichlorobenzyl mercaptan followed by 40 ml of boron trifluoride etherate. The mixture was stirred at 80-85°C for 4 days. The excess reagent was removed under vacuum at 110°C, and the remaining oil poured into 200 ml of 0.5N hydrochloric acid and 200 ml of ether. The mixture was allowed to stand for 18 hours, the ether decanted and two further 200 ml portions of ether added and decanted. The precipitate was filtered off, washed with 75 ml of water and three 125 ml portions of ether and then dried to an apparent mixed salt. A portion of the salt was basified in aqueous ammonium hydroxide, extracted with ether, washed with water and sodium chloride solution, and then dried over magnesium sulfate. The ether solution was treated with ethereal hydrogen bromide to give a salt. This was washed with ether and dried. a white powder of 4-(2,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine hydrobromide, m.p. 208.5-210°C. Analysis:' Calculated for Cig<H>20Cl2FNS-HBr: 49.05%C, 4.55%H, 3.01%N. Found: 48.87%C, 4.52%H, 2.96%N.

b. 0,3 g natriumhydrid (50%) ble vasket med heksan under nitrogen og oppvarmet ved 80°C med 11 ml tørr dimetylsulfoksyd i 30 minutter. Deretter tilsatte man på en gang b. 0.3 g of sodium hydride (50%) was washed with hexane under nitrogen and heated at 80°C with 11 ml of dry dimethylsulfoxide for 30 minutes. It was then added all at once

1,68 g av den frie basen 4-(2,4-diklorbenzylthio)-4-(2-fluor-fenyl) -1-metylpiperidin fra eksempel 47a i 7,3 ml tørr DMSO, 1.68 g of the free base 4-(2,4-dichlorobenzylthio)-4-(2-fluoro-phenyl)-1-methylpiperidine from Example 47a in 7.3 ml of dry DMSO,

og varmekilden ble fjernet. Blandingen ble rørt under nitrogen og langsom avkjøling ti 1 - romtemperatur i løpet av 45 minutter, deretter helt over .i is og ekstrahert med 50 ml eter og 150 ml diklormetan. De samlede organiske faser ble vasket med to 100 ml and the heat source was removed. The mixture was stirred under nitrogen and slowly cooled to room temperature over 45 minutes, then poured onto ice and extracted with 50 ml of ether and 150 ml of dichloromethane. The combined organic phases were washed with two 100 ml

porsjoner av vann og en 25 ml porsjon av natriumkloridoppløs-ning og deretter tørket over magnesiumsulfat til en olje. Denne portions of water and a 25 ml portion of sodium chloride solution and then dried over magnesium sulfate to an oil. This

. ble kromatografert på aluminiumoksyd med eter og man fikk på. was chromatographed on aluminum oxide with ether and obtained

ny en olje. Oljen i eter ble behandlet med eterholdig hydrogenbromid til et salt. Dette ble vasket med eter og omkrystallisert fra ceton-eter til et,gulaktig-hvitt salt av 3-(2,4-diklorfenyl)-1,3-dihydro-l'-mety1-spiro(benzo(c)thiofen-1,41 - piperidin)-hydrobromid, smp. 259,5-261°C. En del av dette råsaltet ble omkrystallisert tre ganger fra-metanol-aceton-eter, new oil. The oil in ether was treated with ethereal hydrogen bromide to a salt. This was washed with ether and recrystallized from ketone ether to give a yellowish-white salt of 3-(2,4-dichlorophenyl)-1,3-dihydro-1'-methyl-spiro(benzo(c)thiophene-1, 41 - piperidine) hydrobromide, m.p. 259.5-261°C. A portion of this crude salt was recrystallized three times from methanol-acetone-ether,

og smeltepunktet var da 260-261°C-and the melting point was then 260-261°C-

Analyse:Analysis:

Beregnet for ClgHigCl2NS•HBr: 51,26%C, 4,53%H, 3,15%N, 15,93%C1. Funnet: . 51,43%C, 4,56%H, 3,15%N, 15,65%C1. Eksempel 48 Calculated for ClgHigCl2NS•HBr: 51.26%C, 4.53%H, 3.15%N, 15.93%C1. Found: . 51.43% C, 4.56% H, 3.15% N, 15.65% Cl. Example 48

1,34 g 1,3-dihydro-3-(3-metylfenyl)-1<1->fenoksykarbonyl-spiro- [benzo (c) thiof en-1 , 4 ' -piperidin ] fra eksempel 44 i 22 ml etylenglykol ble under nitrogen ved 150°C tilsatt 3,44 g 85% vandig natriumhydroksyd. Blandingen ble rørt ved 160°C i 40.min. og så helt over i 50 ml isvann, fortynnet til 120 ml og ekstrahert med to 50 ml porsjoner av diklormetan. Det samlede diklor-metanekstrakt ble vasket med to 50 ml porsjoner av vann og en 1.34 g of 1,3-dihydro-3-(3-methylphenyl)-1<1->phenoxycarbonyl-spiro-[benzo(c)thiophene-1,4'-piperidine] from Example 44 in 22 ml of ethylene glycol was under nitrogen at 150°C added 3.44 g of 85% aqueous sodium hydroxide. The mixture was stirred at 160°C for 40 minutes. and then poured into 50 ml of ice water, diluted to 120 ml and extracted with two 50 ml portions of dichloromethane. The combined dichloromethane extract was washed with two 50 ml portions of water and one

20 ml porsjon av mettet natriumkloridoppløsning og deretter tørket over magnseiumsulfat til en olje. Denne ble renset ved utrøring og avhelling av en 50 ml porsjon og to 25 ml porsjo- 20 ml portion of saturated sodium chloride solution and then dried over magnesium sulfate to an oil. This was purified by stirring and decanting a 50 ml portion and two 25 ml portions.

ner av kokende heksan. Den fordampede'heksanen gir en oljener of boiling hexane. The evaporated'hexane gives an oil

(fri base) som ble oppløst i eter, behandlet med eterholdig maleinsyre og omkrystallisert fra aceton til et hvitt pulver av 1,3-dihydro-3-(3-mety1fenyl)spiro-[benzo(c)thiofen-1,4'-piperidin]-maleat, smp. 175-176°C. (free base) which was dissolved in ether, treated with ethereal maleic acid and recrystallized from acetone to give a white powder of 1,3-dihydro-3-(3-methylphenyl)spiro-[benzo(c)thiophene-1,4'- piperidine] maleate, m.p. 175-176°C.

Analyse:Analysis:

Beregnet for CigH21SN-C4H404: 67,14%C, 6,12%H, 3,41%N.Calculated for C 12 H 21 SN-C 4 H 4 O 4 : 67.14%C, 6.12%H, 3.41%N.

Funnet: 67,29%C, 6,13%H, 3,30%N. Found: 67.29%C, 6.13%H, 3.30%N.

Eksempel 49Example 49

4,02 g av den frie basen 3-(2-klorfenyl)-1'-[3-(4-fluorbenzoyl)propyl]-l,3-dihydrospiro-[benzo(c)thiofen-1,4-piperidin]-etylenketal fra eksempel 46 i 250 ml eter med 15 ml metanol ble tilsatt 120 ml eterholdig.hydrogenbromidoppløsning. Reaksjonsblandingen ble rørt i- 2 timer, hvoretter man tilsatte 4.02 g of the free base 3-(2-chlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiophene-1,4-piperidine]- ethylene ketal from example 46 in 250 ml of ether with 15 ml of methanol was added to 120 ml of ethereal hydrogen bromide solution. The reaction mixture was stirred for 2 hours, after which it was added

120 ml av en 1:4 blanding av 58% ammoniumhydroksyd og vann.120 ml of a 1:4 mixture of 58% ammonium hydroxide and water.

Dette løste alt det faste stoffet. Lagene ble'skilt, og eterlaget vasket med tre 100 ml porsjoner av vann og en 25 ml porsjon av mettet vandig natriumkloridoppløsning, og det hele ble tørket over magnesiumsulfat til.et fast stoff. Dette.ble utrørt i en blanding av 125 ml eter og 64 ml av en 15:1 blanding av vann og 58% ammoniumhydroksyd i løpet av 1 time. Lagene ble . skilt, og det vandige lag vasket med to 50 ml porsjoner av eter og så filtrert til. et fast stoff. De samlede eteroppløsninger ble vasket med vann og natriumkloridoppløsning, tørket, fordampet og det faste stoff omkrystallisert fra etylacetat og slått sammen, hvorved man fikk et fast stoff av 3-(2-klorfenyl)-1'-[3-(4-fluorbenzoylpropyl]-dihydrospiro-[benzo (c)thiofen-1,4'-piperidin], smp. 144-148°C. This dissolved all the solids. The layers were separated and the ether layer washed with three 100 mL portions of water and one 25 mL portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate to a solid. This was stirred in a mixture of 125 ml of ether and 64 ml of a 15:1 mixture of water and 58% ammonium hydroxide during 1 hour. The teams became . separated, and the aqueous layer washed with two 50 ml portions of ether and then filtered again. a solid substance. The combined ether solutions were washed with water and sodium chloride solution, dried, evaporated and the solid recrystallized from ethyl acetate and combined to give a solid of 3-(2-chlorophenyl)-1'-[3-(4-fluorobenzoylpropyl] -dihydrospiro-[benzo (c)thiophene-1,4'-piperidine], mp 144-148°C.

Analyse:Analysis:

Beregnet for C2gH.27ClFNOS: 70,07%C, 5,67%H, 2,92%N, 7,39%C1. Funnet: .69,8140, 5 , 54%H, 2,79%N, 7,29%C1. Eksempel 50 Calculated for C2gH.27ClFNOS: 70.07%C, 5.67%H, 2.92%N, 7.39%C1. Found: .69.8140, 5 , 54%H, 2.79%N, 7.29%C1. Example 50

5,25 .g av den frie basen 1,3-dihydro-3-(3-metylfenyl)-spiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 48 i 65 ml siltørket dimetylformamid ble tilsatt 5,4 3 g yklor-p-fluor-butyrofenonetylenketal og deretter 3,6 g natriumbikarbonat og 3,6. g. kaliumjodid. Blandingen ble rørt ved 85°C i 24 timer, 5.25 g of the free base 1,3-dihydro-3-(3-methylphenyl)-spiro-[benzo(c)thiophene-1,4'-piperidine] from example 48 in 65 ml of sieve-dried dimethylformamide was added 5 .4 3 g of ychloro-p-fluoro-butyrophenoneethylene ketal and then 3.6 g of sodium bicarbonate and 3.6. g. potassium iodide. The mixture was stirred at 85°C for 24 hours,

så fortynnet med 130 ml kloroform og filtrert. Oppløsningsmid-let ble fjernet, og den gjenværende oljen ble delt mellom 250 ml diklormetan og 150 ml vann og en 35 ml porsjon av mettet natriumkloridoppløsning. Den ble så tørket over magnesiumsulfat til en olje. Denne ble kromatografert på aluminiumoksyd med eter og så omdannet til et maleatsalt ved behandling med maleinsyreholdig eter. Omkrystallisering fra aceton-eter gir 1'-[3-(4-fluorbenzoy1)propyl]-1,3-dihydro-3-(3-mety1fenyl)spiro-[benzo (c) thiofen-1, 4 ' -piperidin ] -etylenketalmaleat, smp . 15 5-15 7°C. Analyse': Beregnet for C31H34<F>N02S•C4H404: 67, 84%C, 6,18%H, 2,26%N.. Funnet: 67,76%C, 6,19%H, 2,15%N. Eksempel 51 then diluted with 130 ml of chloroform and filtered. The solvent was removed and the remaining oil was partitioned between 250 ml of dichloromethane and 150 ml of water and a 35 ml portion of saturated sodium chloride solution. It was then dried over magnesium sulfate to an oil. This was chromatographed on aluminum oxide with ether and then converted to a maleate salt by treatment with ether containing maleic acid. Recrystallization from acetone-ether gives 1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(3-methylphenyl)spiro-[benzo(c)thiophene-1,4'-piperidine] - ethylene ketal maleate, m.p. 15 5-15 7°C. Analysis': Calculated for C31H34<F>N02S•C4H404: 67, 84%C, 6.18%H, 2.26%N.. Found: 67.76%C, 6.19%H, 2.15% N. Example 51

8,5 g fenylklorformat i 130 ml tørr diklormetan under nitrogen ble tilsatt en oppløsning av 15,56 g av den frie ba- 8.5 g of phenylchloroformate in 130 ml of dry dichloromethane under nitrogen was added to a solution of 15.56 g of the free base

sen 3-(2,4-diklorbenzylthio)-1,3-dihydro-1'-metylspiro-[benzo-(c)thiofen-1,4'-piperidin] fra eksempel 47 i 100 ml tørr diklor- late 3-(2,4-dichlorobenzylthio)-1,3-dihydro-1'-methylspiro-[benzo-(c)thiophene-1,4'-piperidine] from Example 47 in 100 ml of dry dichloro-

metan i løpet av 15 minutter. Blandingen ble rørt ved romtemperatur i 21 timer, så fortynnet med 450 ml diklormetan, vasket med to 300 ml porsjoner av .10% vandig natriumhydroksyd-oppløsning, to 300 ml porsjoner av vann og en 100 ml porsjon av natriumkloridoppløsning og så tørket over magnesiumsulfat, hvorved man fikk en olje. Denne ble kromatografert på silisiumdioksydgel med diklormetan som elueringsmiddel, og man fikk en klar olje av 3-(2,4-diklorfenyl)-1,3-dihydro-l'-fenoksykarbonylspiro-[benzo(c)thiofen-1,4<1->piperidin]. Analyse: Beregnet for C25H21C12N02S: 63,84%C, 4,50%H, ' 2,98%N. Funnet: 63,71%C, 4,52%H, 2,79%N. methane within 15 minutes. The mixture was stirred at room temperature for 21 hours, then diluted with 450 ml of dichloromethane, washed with two 300 ml portions of .10% aqueous sodium hydroxide solution, two 300 ml portions of water and one 100 ml portion of sodium chloride solution and then dried over magnesium sulfate, whereby an oil was obtained. This was chromatographed on silica gel with dichloromethane as eluent, and a clear oil of 3-(2,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4<1 ->piperidine]. Analysis: Calculated for C25H21C12N02S: 63.84%C, 4.50%H, ' 2.98%N. Found: 63.71%C, 4.52%H, 2.79%N.

Eksempel 52Example 52

En oppløsning av 2,85 g av den frie basen l'-[3-(4-fluorbenzoy1)propyl]-l,3-dihydro-3-(2-metylfeny1)spiro-[benzo-(c)thiofen-1,4<1->piperidin]-etylenketal fra eksempel 42, 30 ml absolutt etanol og 30 ml 3N HCl-oppløsning ble kokt under til-bakeløp i 45 minutter. Reaksjonsblandingen ble avkjølt, gjort basisk med 40% vandig NaOH-oppløsning og ekstrahert med metylenklorid. Metylenkloridfraksjonene ble slått sammen, vasket med vann og tørket over magnesiumsulfat. Oppløsningen ble så filtrert og fordampet til et fast stoff som ble omkrystallisert fra etylacetat og man fikk det .rene produktet av 1'-[3-( 4-f luorbenzoyl) propyl ]-l, 3-dihydro- 3- (2-mety.lf eny 1) spiro-[benzo(c)thiofen-1,4'-piperidin], smp. 143-145°C. .Analyse: Beregnet for C29H3QFNOS: 75, 78%C, 6,58%H, 3,05%N-.. A solution of 2.85 g of the free base 1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(2-methylphenyl)spiro-[benzo-(c)thiophene-1, 4<1->piperidine]-ethylene ketal from Example 42, 30 ml of absolute ethanol and 30 ml of 3N HCl solution were refluxed for 45 minutes. The reaction mixture was cooled, basified with 40% aqueous NaOH solution and extracted with methylene chloride. The methylene chloride fractions were combined, washed with water and dried over magnesium sulfate. The solution was then filtered and evaporated to a solid which was recrystallized from ethyl acetate to give the pure product of 1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(2-methyl .lf eny 1) spiro-[benzo(c)thiophene-1,4'-piperidine], m.p. 143-145°C. .Analysis: Calculated for C29H3QFNOS: 75, 78%C, 6.58%H, 3.05%N-..

Funnet: 75,51%C, 6,70%H, 2,85%N. Found: 75.51%C, 6.70%H, 2.85%N.

Eksempel 53Example 53

15,12 g 3-(2,4-diklorfeny1)-1,3-dihydro-l<1->fenoksy-karbonylspiro- [benzo ( c) thiof en-1 , 4 ' -piperidin ] fra eksempel 51 i 216 ml etylenglykol ved 150°C under nitrogen ble tilsatt 34,2 g 85% kaliumhydroksydpellets. Blandingen ble rørt ved 160°C i 45 minutter, deretter helt over i 1,4 liter vann og ekstrahert med tre 350 ml porsjoner diklormetan. De samlede diklormetanekstrakter ble vasket med to 400 ml porsjoner av vann og en 100 ml porsjon av mettet vandig natriumkloridopp-løsning og så tørket over magnesiumsulfat til en olje. Oljen ble renset ved avhelling med tre 225 ml porsjoner av kokende 15.12 g of 3-(2,4-dichlorophenyl)-1,3-dihydro-1<1->phenoxy-carbonylspiro-[benzo(c)thiophene-1,4'-piperidine] from Example 51 in 216 ml ethylene glycol at 150°C under nitrogen was added to 34.2 g of 85% potassium hydroxide pellets. The mixture was stirred at 160°C for 45 minutes, then poured into 1.4 liters of water and extracted with three 350 ml portions of dichloromethane. The combined dichloromethane extracts were washed with two 400 ml portions of water and one 100 ml portion of saturated aqueous sodium chloride solution and then dried over magnesium sulfate to an oil. The oil was purified by decanting with three 225 ml portions of boiling

heksan, hvorved man fikk et fast stoff. En del av dette ble oppløst i. eter og behandlet med maleinsyreholdig eter til et salt. Saltet ble vasket med eter og omkrystallisert fra metanol-aceton-eter til et hvitt pulver av 3-(2,4-diklorfeny1)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-maleat, hexane, whereby a solid was obtained. A portion of this was dissolved in ether and treated with ether containing maleic acid to form a salt. The salt was washed with ether and recrystallized from methanol-acetone-ether to give a white powder of 3-(2,4-dichlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine]-maleate ,

smp. 171-172,5°C. m.p. 171-172.5°C.

Analyse:Analysis:

Beregnet for C18H17C12NS•C4H404: 56,66%C, 4,54%H, 3,00%N, 15,20%C1. Funnet: 56, 49%'C, 4,54%H, 2,81%N, 14,99%C1. Eksempel 54 3,0 g av.den frie basen 3-(2,4-diklorfenyl)-1,3-dihydro-spiro- [benzo(c)thiofen-1,4'-piperidin] fra eksempel 53 i 35 ml siltørket dimetylformamid ble tilsatt 2,6 2 g y~klor-p-fluor-butyrofenonetylenketal fulgt av 1,7 g natriumbikarbonat og 1,7 g kaliumjodid. Reaksjonsblandingen ble så rørt.yed 80-90°C i 20 timer. Blandingen ble fortynnet med 75 ml kloroform, filtrert og fordampet på en roterende fordamper véd 75°C til en'olje. Denne ble så delt mellom 125 ml diklormetan og 85 ml vann. Blandingen ble fortynnet med 10 ml mettet vandig natriumbikar-bonatoppløsning, og det organiske lag ble utskilt og vasket med en 80 ml porsjon av vann og en 30 ml porsjon av mettet natriumkloridoppløsning. Diklormetanoppløsningen ble .tørket og fordampet til en olje. Denne ble kromatografert på aluminiumoksyd med eter, og en del av den resulterende oljen ble plassert i eter og behandlet med eterholdig oksalsyre til et salt. Saltet ble vasket med eter og omkrystallisert fra metanol-aceton-eter til et hvitt pulver av 3-(2,4-diklorfenyl)-1<1->[3-(4-fluorbenzoy1)-propyl]-l,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-etylenketaloksalat, smp. 164-165°C. Analyse: Beregnet for C3Q<H>30Cl2FNO2S•C2H204: 59,26%C, 4,97%H, 2,16%N. Funnet: 59,15%C, 4',81%H, 2,11%N. Eksempel 55 Calculated for C18H17C12NS•C4H4O4: 56.66%C, 4.54%H, 3.00%N, 15.20%C1. Found: 56, 49%'C, 4.54%H, 2.81%N, 14.99%C1. Example 54 3.0 g of the free base 3-(2,4-dichlorophenyl)-1,3-dihydro-spiro-[benzo(c)thiophene-1,4'-piperidine] from example 53 in 35 ml sieve-dried of dimethylformamide was added 2.6 2 g of γ-chloro-p-fluoro-butyrophenoneethylene ketal followed by 1.7 g of sodium bicarbonate and 1.7 g of potassium iodide. The reaction mixture was then stirred at 80-90°C for 20 hours. The mixture was diluted with 75 ml of chloroform, filtered and evaporated on a rotary evaporator at 75°C to an oil. This was then divided between 125 ml of dichloromethane and 85 ml of water. The mixture was diluted with 10 ml of saturated aqueous sodium bicarbonate solution and the organic layer was separated and washed with an 80 ml portion of water and a 30 ml portion of saturated sodium chloride solution. The dichloromethane solution was dried and evaporated to an oil. This was chromatographed on alumina with ether, and a portion of the resulting oil was placed in ether and treated with ethereal oxalic acid to a salt. The salt was washed with ether and recrystallized from methanol-acetone-ether to give a white powder of 3-(2,4-dichlorophenyl)-1<1->[3-(4-fluorobenzoyl)-propyl]-1,3-dihydrospiro -[benzo(c)thiophene-1,4'-piperidine]-ethylene ketaloxalate, m.p. 164-165°C. Analysis: Calculated for C3Q<H>30Cl2FNO2S•C2H204: 59.26%C, 4.97%H, 2.16%N. Found: 59.15%C, 4'.81%H, 2.11%N. Example 55

a. 26,33 g 4-(2-fluorfenyl)-4-hydroksy-l-metylpiperi-a. 26.33 g 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperi-

din fra eksempel la med 20 ml (ca. 23,3 g) m-fluorbenzylmerkap-your from example la with 20 ml (approx. 23.3 g) of m-fluorobenzylmercap-

tan i 25 ml iseddik ble tilsatt 33 ml bortrifluoridetan. Blandingen ble rørt' ved 65-68°C i 44 timer hvoretter man tilsatte ytterligere 17 ml bortrifluorideterat og røring ved 65-68°C tan in 25 ml of glacial acetic acid was added to 33 ml of boron trifluoride ethane. The mixture was stirred at 65-68°C for 44 hours, after which a further 17 ml of boron trifluoride etherate was added and stirring at 65-68°C

ble fortsatt i ytterligere 3 døgn. Overskudd av oppløsningsmiddel was continued for a further 3 days. Excess solvent

ble fjernet under redusert trykk til 110°C. Residumet ble blandet med 450 ml 0,5N HC1 og 175 ml eter, og man fikk dannet en olje. Oljen og vannlaget ble vasket med avhelling med eter, hvoretter den vandige syren ble forsiktig avhelt fra oljen. Oljen ble plassert under vann, behandlet ved pH 9-10 med ammoniumhydroksyd og ekstrahert méd eter. Eteroppløsningen ble vasket méd vann inntil nøytral reaksjon, så helt over i en oppløsning av 30 ml 4 8% hydrogenbromid fortynnet til 350 ml was removed under reduced pressure to 110°C. The residue was mixed with 450 ml of 0.5N HCl and 175 ml of ether, and an oil was formed. The oil and aqueous layer were washed by decantation with ether, after which the aqueous acid was carefully decanted from the oil. The oil was placed under water, treated at pH 9-10 with ammonium hydroxide and extracted with ether. The ether solution was washed with water until the reaction was neutral, then poured into a solution of 30 ml of 4 8% hydrogen bromide diluted to 350 ml

og man fikk dannet et salt. Dette bie frafiltrert, vasket med en liten mengde vann og en større mengde eter til et hvitt salt av 4-(3-fluorbenzylthio)-4-(2-fluorfenyl)-1-metylpiperidin-hydrobromid, smp. 176-178,5°C. En tre ganger omkrystallisert prøve (metanbl-aceton-eter) smelter ved 178-179°C. Analyse: and a salt was formed. This was filtered off, washed with a small amount of water and a larger amount of ether to give a white salt of 4-(3-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine hydrobromide, m.p. 176-178.5°C. A three-times recrystallized sample (methanebl-acetone-ether) melts at 178-179°C. Analysis:

Beregnet for C19H21F2NS•HBr: 55,08%C, 5,35%H, 3,38%N.Calculated for C19H21F2NS•HBr: 55.08%C, 5.35%H, 3.38%N.

Funnet: 55,05%C, 5/38%H, 3,38%N. Found: 55.05%C, 5/38%H, 3.38%N.

b. 1,404 g av natriumhydrid (fra 2,87 g av en 50% dispersjon) ble under nitrogen tilsatt 120 ml siltørket dimetylsulfoksyd. Blandingen ble rørt ved 80-85°C i 35 minutter og så avkjølt til romtemperatur. En oppløsning av 14,0 g av den frie basen 4-(3-fluorbenzylthio)-4-(2-fluorfeny1)-1-metylpiperidin fra eksempel 55a i 47 ml DMSO ble tilsatt i' løpet av 60 sekun-der og oppløsningen rørt i en time. Reaksjonsblandingen ble så helt over i 700 ml isvann og ekstrahert med tre 200 ml porsjoner av diklormetan. De samlede diklormetanekstrakter ble vasket med tre 300 ml porsjoner av. vann og■en 75 ml porsjon med mettet natriumkloridoppløsning og så tørket over magnesiumsulfat til en olje. Denne ble kromatografert1 på en aluminiumoksydkolonne med eter og man fikk utfelt krystaller. En del av disse ble i eter behandlet med eterholdig maleinsyre. Det resulterende salt ble vasket med eter og tørket til et pulver av 3-(3-fluorfeny1)-1,3-dihydro-1'-metylspiro-[benzo(c)thio fen-1,4'-piperidin]-maleat, smp. 137-140°C. En porsjon som var omkrystallisert to ganger smelter ved 138,5-140,5°C. Ved konti-nuerlig oppvarming får man utviklet en ny krystallinsk form som faller sammen i området ved 175-180°C. b. 1.404 g of sodium hydride (from 2.87 g of a 50% dispersion) was added under nitrogen to 120 ml of sieve-dried dimethyl sulfoxide. The mixture was stirred at 80-85°C for 35 minutes and then cooled to room temperature. A solution of 14.0 g of the free base 4-(3-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine from Example 55a in 47 ml of DMSO was added over 60 seconds and the solution stirred for one hour. The reaction mixture was then poured into 700 ml of ice water and extracted with three 200 ml portions of dichloromethane. The combined dichloromethane extracts were washed with three 300 ml portions of water and a 75 ml portion of saturated sodium chloride solution and then dried over magnesium sulfate to an oil. This was chromatographed1 on an alumina column with ether and precipitated crystals were obtained. A portion of these were treated in ether with ethereal maleic acid. The resulting salt was washed with ether and dried to a powder of 3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c)thiophen-1,4'-piperidine]-maleate, m.p. 137-140°C. A portion which was recrystallized twice melts at 138.5-140.5°C. With continuous heating, a new crystalline form is developed which collapses in the range of 175-180°C.

Analyse:Analysis:

Beregnet for C19H2QFNS•C4H404: .64,32%C, 5,63%H, 3,26%N, 4,42%F. Funnet: 64,26%C, 5,58%H, 2,95%N, 4,58%F. Calculated for C19H2QFNS•C4H4O4: .64.32%C, 5.63%H, 3.26%N, 4.42%F. Found: 64.26%C, 5.58%H, 2.95%N, 4.58%F.

Eksempel 56Example 56

3,26 g av den frie basen 3-(2,4-diklorfeny1)-1'-[3-(4-fluorbenzoy1)propyl]-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-etylenketal fra eksempel 54 i 30 ml varm eta- 3.26 g of the free base 3-(2,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiophene-1,4<1 ->piperidine]-ethylene ketal from example 54 in 30 ml of hot eta-

nol ble langsomt tilsatt 30 ml 3N saltsyre. Blandingen ble oppvarmet på et dampbad i 45 minutter. 10 ml ytterligere eta- nol was slowly added to 30 ml of 3N hydrochloric acid. The mixture was heated on a steam bath for 45 minutes. 10 ml additional eta-

nol ble tilsatt og oppvarming fortsatt i 45 minutter. Blandingen ble så avkjølt til romtemperatur og gjort basisk med 40% vandig natr.iumhydroksy dopp løsning. Blandingen ble for- nol was added and heating continued for 45 minutes. The mixture was then cooled to room temperature and made basic with 40% aqueous sodium hydroxy dopp solution. The mixture was pre-

tynnet med 200 ml vann og ekstrahert med tre 80 ml porsjonerdiluted with 200 ml of water and extracted with three 80 ml portions

med diklormetan. De samlede diklormetanekstrakter ble vasket med to 100 ml porsjoner av vann, en 50 ml porsjon av mettet vandig natriumkloridoppløsning og tørket over magnesiumsulfat with dichloromethane. The combined dichloromethane extracts were washed with two 100 ml portions of water, one 50 ml portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate

til en olje. Denne ble oppløst i eter, filtrert gjennom celittto an oil. This was dissolved in ether, filtered through celite

og behandlet med eterholdig maleinsyre til et salt. Saltet ble vasket med eter og omkrystallisert fra aceton-eter til hvitt pulver av 3-(2,4-diklorfeny1)-1'-[3-(4-fluorbenzoy1)propyl]-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-maleat, and treated with ethereal maleic acid to a salt. The salt was washed with ether and recrystallized from acetone-ether to give white powder of 3-(2,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro-[benzo(c) thiophene-1,4'-piperidine]-maleate,

smp. 124-127°C. En prøve som var omkrystallisert tre ganger smeltet ved 127-129°C. m.p. 124-127°C. A sample that had been recrystallized three times melted at 127-129°C.

Analyse: .Analysis: .

Beregnet for C2gH26<C>l2FNOS-C4H4<0>4<:>Calculated for C2gH26<C>l2FNOS-C4H4<0>4<:>

60,96%C, 4,80%H, 2,.22%N, 11,25%C1. 60.96% C, 4.80% H, 2.22% N, 11.25% Cl.

Funnet: 61',13%C, 4,78%H., 2,06%N, 11,02%C1. Found: 61'.13%C, 4.78%H., 2.06%N, 11.02%C1.

Eksempél - 5 7Example - 5 7

5,O g fenylklorformat i 80. ml diklormetan ble tilsatt5.0 g of phenylchloroformate in 80 ml of dichloromethane was added

7,89 g av den frie basen 3-(.3-f luorfenyl)-1, 3-dihydro-l'-metylspiro-[benzo(c)thiofen-1,4<1->piperidin] fra eksempel 55 i 10 ml diklormetan i løpet av 20 minutter. Reaksjonsblandingen ble rørt ved romtemperatur i 21 timer og så fortynnet med 200 ml diklormetan. Den resulterende blanding ble vasket med to 175 ml porsjoner av en 10% vandig natriumhydroksydoppløsning, to 150 ml porsjoner av vann og en 70 ml porsjon av mettet vandig-natrium-kloridoppløsning og så tørket over magnesiumsulfat til en olje. Denne ble kromatografert på silisiumdioksydgel med diklormetan som elueringsmiddel til en olje som ved utkrystallisering gir 3-(3rfluorfeny1)-1,3-dihydro-11 - fenoksykarbonylspiro-[benzo(c)-thiofen-1,4<1->piperidin], smp. 134-142°C. En,porsjon ble omkrystallisert to ganger fra toluen:heksan og smelter da ved 144-146°C. 7.89 g of the free base 3-(.3-fluorophenyl)-1,3-dihydro-1'-methylspiro-[benzo(c)thiophene-1,4<1->piperidine] from Example 55 in 10 ml of dichloromethane during 20 minutes. The reaction mixture was stirred at room temperature for 21 hours and then diluted with 200 ml of dichloromethane. The resulting mixture was washed with two 175 ml portions of a 10% aqueous sodium hydroxide solution, two 150 ml portions of water and one 70 ml portion of saturated aqueous sodium chloride solution and then dried over magnesium sulfate to an oil. This was chromatographed on silica gel with dichloromethane as eluent to an oil which, upon crystallization, gives 3-(3-fluorophenyl)-1,3-dihydro-11-phenoxycarbonylspiro-[benzo(c)-thiophene-1,4<1->piperidine], m.p. 134-142°C. A portion was recrystallized twice from toluene:hexane and then melts at 144-146°C.

Analyse:Analysis:

Beregnet for C25H22FN02S: 71,58%C, 5,29%H, 3,34%N.Calculated for C25H22FN02S: 71.58%C, 5.29%H, 3.34%N.

Funnet: 71,60%C, 5,33%H, 3,22%N. Found: 71.60%C, 5.33%H, 3.22%N.

Eksempel 58Example 58

6,97 g 3-(3-fluorfenyl)-i,3-dihydro-l'-fenoksykarbo-nylspiro- [benzo ( c) thiof en-1 , 4 ' -piperidin ] fra eksempel 57 i: 100 ml etylenglykol under nitrogen ved 150°C ble tilsatt 16 g 85% kaliumhydroksydpellets. Blandingen ble rørt ved 160°C i 45 minutter. Oppløsningen ble så helt over i 225 ml isvann, fortynnet til 500 ml og ekstrahert med tre 175 ml porsjoner med diklormetan. De samlede diklormetanekstrakter ble. vasket med 200 ml porsjoner med vann og en 50 ml porsjon med mettet vandig natriumkloridoppløsning og så tørket over magnesiumsulfat til et fast stoff. Den frie base i eter ble behandlet med eterholdig maleinsyre til et salt. Saltet ble vasket med eter og omkrystallisert fra metanol-aceton-eter til et hvitt pulver av 3-(3-fluorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-l,4'-piperidin]-maleat, smp. 188-188,5°C. 6.97 g of 3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-[benzo(c)thiophene-1,4'-piperidine] from Example 57 in: 100 ml of ethylene glycol under nitrogen at 150°C, 16 g of 85% potassium hydroxide pellets were added. The mixture was stirred at 160°C for 45 minutes. The solution was then poured into 225 ml of ice water, diluted to 500 ml and extracted with three 175 ml portions of dichloromethane. The combined dichloromethane extracts were washed with 200 ml portions of water and a 50 ml portion of saturated aqueous sodium chloride solution and then dried over magnesium sulfate to a solid. The free base in ether was treated with ethereal maleic acid to give a salt. The salt was washed with ether and recrystallized from methanol-acetone-ether to give a white powder of 3-(3-fluorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine]-maleate, m.p. . 188-188.5°C.

Analyse:Analysis:

Beregnet for C18H18FNS: 63,51%C, 5,34%H, 3,37%N,'4,57%F. Funnet: 63,53%C, 5,37%H, 3,31%N, 4,45%F. Eksempel 59 Calculated for C18H18FNS: 63.51%C, 5.34%H, 3.37%N,'4.57%F. Found: 63.53%C, 5.37%H, 3.31%N, 4.45%F. Example 59

2,75 g (9,19 millimol) av den frie basen 3-(3-fluor-fenyl) -1, 3-dihydrospiro- [benzo (c) thiofen-1, 4 1 -piperidin] 2.75 g (9.19 millimoles) of the free base 3-(3-fluoro-phenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,41-piperidine]

fra eksempel 58 i 47 ml siltørket dimetylformamid ble tilsatt 2,81 gY~klor-p-fluorbutyrofenonetylenketal samt 1,82 g kaliumjodid og 1,82 g natriumbikarbonat. Blandingen ble rørt ved 65-90°C i 20 timer, så fortynnet med 75 ml kloroform, filtrert og fordampet i et roterende fordampningsapparat ved 75°C til en olje. Oljen ble delt mellom 125 ml diklormetan og 85 ml vann. En 10 ml porsjon av en mettet vandig natriumbikarbonatoppløs-ning ble tilsatt, og oppløsningene skilt. Det organiske lag ble vasket med en 80 ml porsjon vann og en 30 ml porsjon av en mettet vandig natriumkloridoppløsning og så tørket over magnesiumsulfat til en olje. Oljen ble kromatografert på aluminiumoksyd med eter og ga da 3-(3-fluorfeny1)-1'-[3-(4-fluorbenzoy1)-propyl]-l,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-etylenketal. from example 58, 2.81 g of Y~chloro-p-fluorobutyrophenoneethylene ketal as well as 1.82 g of potassium iodide and 1.82 g of sodium bicarbonate were added to 47 ml of sieve-dried dimethylformamide. The mixture was stirred at 65-90°C for 20 hours, then diluted with 75 ml of chloroform, filtered and evaporated in a rotary evaporator at 75°C to an oil. The oil was partitioned between 125 ml of dichloromethane and 85 ml of water. A 10 ml portion of a saturated aqueous sodium bicarbonate solution was added and the solutions separated. The organic layer was washed with an 80 ml portion of water and a 30 ml portion of a saturated aqueous sodium chloride solution and then dried over magnesium sulfate to an oil. The oil was chromatographed on alumina with ether to give 3-(3-fluorophenyl)-1'-[3-(4-fluorobenzoyl)-propyl]-1,3-dihydrospiro-[benzo(c)thiophene-1,4< 1->piperidine]-ethylene ketal.

Omkrystallisering fra cykloheksan-pentan gir en prøve som smelter ved 121,5-123°C. Recrystallization from cyclohexane-pentane gives a sample melting at 121.5-123°C.

Analyse:Analysis:

Beregnet for<C>3()H31F2N02S: 70,98%C, 6,17%H, 2,76%N.Calculated for <C>3()H31F2N02S: 70.98%C, 6.17%H, 2.76%N.

Funnet: 70,97%C, 6,20%H, 2,43%N. Found: 70.97%C, 6.20%H, 2.43%N.

Eksempel 60Example 60

3,75 g 3-(3-fluorfenyl)-1'-[3-(4-fluorbenzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiofen-1,4<1->piperidin]-etylenketal fra eksempel 59 i 38 ml etanol ble tilsatt 38 ml 3N saltsyre. Blandingen ble kokt under .tilbakeløp i 2 timer og så hensatt ved romtemperatur i 16 timer. Oppløsningen ble så fortynnet med 100 ml vann og et par ml 40% vandig natriumhydroksydopp-løsning ble så tilsatt til en pH på 11. Blandingen ble så fortynnet med 175 ml vann og ekstrahert med tre 175 ml porsjoner av en diklormetanoppløsning. De samlede diklormetanekstrakter ble vasket med to 125 ml porsjoner med vann og en 60 ml porsjon av en mettet vandig natriumkloridoppløsning og så tørket over magnesiumsulfat til en olje. Oljen ble så eter-behandlet med eterholdig maleinsyre, og det resulterende salt vasket med eter og omkrystallisert fra aceton-eter til et hvitt krystallinsk pulver av 1'-[3-(4-fluorbenzoyl)propyl]-' 3-(3-fluorfenyl)-l,3-dihydrospiro-[benzo(c)thiofen-1,41-piperidin j-maleat, smp. 149-150°C. 3.75 g 3-(3-fluorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro-[benzo(c)thiophene-1,4<1->piperidine]-ethylene ketal from example 59 in 38 ml of ethanol was added 38 ml of 3N hydrochloric acid. The mixture was refluxed for 2 hours and then left at room temperature for 16 hours. The solution was then diluted with 100 ml of water and a few ml of 40% aqueous sodium hydroxide solution was then added to a pH of 11. The mixture was then diluted with 175 ml of water and extracted with three 175 ml portions of a dichloromethane solution. The combined dichloromethane extracts were washed with two 125 ml portions of water and one 60 ml portion of a saturated aqueous sodium chloride solution and then dried over magnesium sulfate to an oil. The oil was then etherified with ethereal maleic acid, and the resulting salt washed with ether and recrystallized from acetone-ether to give a white crystalline powder of 1'-[3-(4-fluorobenzoyl)propyl]-' 3-(3-fluorophenyl) )-1,3-dihydrospiro-[benzo(c)thiophene-1,41-piperidine j-maleate, m.p. 149-150°C.

Analyse:Analysis:

Beregnet for C2gH27<F>2NOS•C4H404: 66,31%C, 5,39%H, 2,42%N, 6,56%F. Funnet: 66,35%C, 5,54%H, 2,14%N, 6,61%F. Calcd for C2gH27<F>2NOS•C4H4O4: 66.31%C, 5.39%H, 2.42%N, 6.56%F. Found: 66.35%C, 5.54%H, 2.14%N, 6.61%F.

Eksempel 61Example 61

En oppløsning av 3,10 g av den frie basen 1,3-dihydro-3-(4-metylfenyl)spiro-[benzo(c)thiofen-1,4'-piperidin] fra eksempel 40 i 54 ml dimety lformamid ble tilsatt 3,21 g yklo.r-p-fluorbutyrofenonetylenketal, 2,07 g kaliumjodid og 2,07 g natriumbikarbonat. Reaksjonsblandingen ble rørt og oppvarmet ved 65-90°C i 18 timer. Den ble så fortynnet med 75 ml kloroform, filtrert og fordampet til en olje. Oljen ble så.delt mellom 150 ml diklormetan og 125 ml vann. Det■organiske lag ble vasket med vann og en vandig natriumkloridoppløsning og så tørket over magnesiumsulfat. Oppløsningen ble filtrert og fordampet til en olje som så ble kolonnekromatografert på aluminiumoksyd med eter som elueringsmi.ddel. En prøve av den re sulterende frie base ble omdannet til oksalatsaltet av l'-[3-(4-fluorbenzoyl)propyl]-3-(4-metylfeny1)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-etylenketaloksalat. A solution of 3.10 g of the free base 1,3-dihydro-3-(4-methylphenyl)spiro-[benzo(c)thiophene-1,4'-piperidine] from Example 40 in 54 ml of dimethylformamide was added 3.21 g of cyclo.r-p-fluorobutyrophenoneethylene ketal, 2.07 g of potassium iodide and 2.07 g of sodium bicarbonate. The reaction mixture was stirred and heated at 65-90°C for 18 hours. It was then diluted with 75 ml of chloroform, filtered and evaporated to an oil. The oil was then partitioned between 150 ml of dichloromethane and 125 ml of water. The organic layer was washed with water and an aqueous sodium chloride solution and then dried over magnesium sulfate. The solution was filtered and evaporated to an oil which was then column chromatographed on alumina with ether as eluent. A sample of the resulting free base was converted to the oxalate salt of 1'-[3-(4-fluorobenzoyl)propyl]-3-(4-methylphenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1, 4'-piperidine]-ethylene ketaloxalate.

Analyse:Analysis:

Beregnet for C31H34FN02S"C2H2°4: 66/76%C'6,11%H, 2,36%N. Funnet: 66,85%C, 6,'12%H, 2,32%N. Calculated for C31H34FN02S"C2H2°4: 66/76%C'6.11%H, 2.36%N. Found: 66.85%C, 6.'12%H, 2.32%N.

Eksempel 62Example 62

En oppløsning av 2,57 g 1<1->[3-(4-fluorbenzoy1)propyl]-1.3- dihydro-3-(4-metylfenyl)spiro-[benzo(c)thiofen-l> 4'-piperidin]-etylenketal fra eksempel 61, 27 ml absolutt etanol og 27 ml 3N HC1 ble oppvarmet på et dampbad i 45 minutter. Blandingen ble avkjølt, fortynnet med 75 ml vann og justert til pH 11 ved hjelp' av en 40% vandig NaOH-oppløsning. Reaksjonsblandingen ble fortynnet med 150 ml vann og ekstrahert med diklormetan. Diklormetanekstraktene ble slått sammen, vasket med vann og natriumkloridoppløsning og så tørket over magnesiumsulfat. Den tørkede diklormetanoppløsning ble filtrert og fordampet til en olje som stivner under pentan. Det filtrerte produkt ble omkrystallisert fra etylacetat og ga da 1<1->[3-(4-fluorbenzoyl)propyl3-1,3-dihydro-3-(4-mety1fenyl)-spiro-[benzo(c)thiofen-1,4'-piperidin], smp. 134-135°C. Analyse: A solution of 2.57 g of 1<1->[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(4-methylphenyl)spiro-[benzo(c)thiophene-1>4'-piperidine] -ethylene ketal from Example 61, 27 ml of absolute ethanol and 27 ml of 3N HCl were heated on a steam bath for 45 minutes. The mixture was cooled, diluted with 75 ml of water and adjusted to pH 11 using a 40% aqueous NaOH solution. The reaction mixture was diluted with 150 ml of water and extracted with dichloromethane. The dichloromethane extracts were combined, washed with water and sodium chloride solution and then dried over magnesium sulfate. The dried dichloromethane solution was filtered and evaporated to an oil which solidifies under pentane. The filtered product was recrystallized from ethyl acetate to give 1<1->[3-(4-fluorobenzoyl)propyl-3-1,3-dihydro-3-(4-methylphenyl)-spiro-[benzo(c)thiophene-1, 4'-piperidine], m.p. 134-135°C. Analysis:

Beregnet for<C>2gH30FNOS: 75,78%C, 6,58%H, 3,05%N.Calculated for <C>2gH30FNOS: 75.78%C, 6.58%H, 3.05%N.

Funnet: 75,61%C, 6,67%H, 3,07%N. Found: 75.61%C, 6.67%H, 3.07%N.

Eksempel 6 3Example 6 3

6,87 g 3-(4-klorfenyl)-1,3-dihydrospiro-[benzo(c)thiofen-1 , 4 ' -piperidin ] fra eksempel 15 i en oppløsning av 33 ml 2-butanon med 33 ml dimetylformamid ble tilsatt 6,04 g y-klor-2.4- difluorbutyrofenonetylenketal fulgt av 6,5 g natriumbikarbonat og 4,08 g kaliumjodid. Reaksjonsblandingen ble rørt ved 7-5-80°C i 18 timer og så tilsatt 400 ml isvann og så ekstrahert med tre 125 ml porsjoner med eter. De samlede eterekstrakter ble vasket med to 150 ml porsjoner vann og en 30 ml porsjon med natriumkloridoppløsning og så tørket over magnesiumsulfat til en olje. Denne ble kromatografert på 300 ml aluminiumoksyd med eter og ga en olje som etter hvert utkrystalliserte seg til et produkt. En del av produktet ble fortynnet med eter, behandlet med eterholdig maleinsyre til et salt. Saltet ble omkrystallisert en gang fra metanol-eter og 6.87 g of 3-(4-chlorophenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4'-piperidine] from Example 15 in a solution of 33 ml of 2-butanone with 33 ml of dimethylformamide was added 6.04 g of γ-chloro-2,4-difluorobutyrophenoneethylene ketal followed by 6.5 g of sodium bicarbonate and 4.08 g of potassium iodide. The reaction mixture was stirred at 7-5-80°C for 18 hours and then 400 ml of ice water was added and then extracted with three 125 ml portions of ether. The combined ether extracts were washed with two 150 ml portions of water and one 30 ml portion of sodium chloride solution and then dried over magnesium sulfate to an oil. This was chromatographed on 300 ml of aluminum oxide with ether and gave an oil which eventually crystallized into a product. A portion of the product was diluted with ether, treated with ethereal maleic acid to a salt. The salt was recrystallized once from methanol-ether and

en gang fra aceton-etylacetat-pentan og ga 3-(4-klorfeny1)-l'-[3-(2,4-difluorbenzoyl)propyl]-1,3-dihydrospiro-[benzo-(c)thiofen-1,4'-piperidin]-etylenketalmaleat, smp. 148-149°C. Analyse: Beregnet for C30H30ClF2NO2S•C4H404: 62,05%C, 5,21%H, 2,13%N. Funnet: 61,94%C, 5,01%H, 2,16%N. Eksempel 64 8,21 g (15,15 millimol) av den frie base 3-(4-klor-•fenyl) -1- [ 3- ( 2 , 4-di f luorbenzoy 1) propyl ] -1, 3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin]-etylenketal fra eksempel 63 once from acetone-ethyl acetate-pentane to give 3-(4-chlorophenyl)-1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydrospiro-[benzo-(c)thiophene-1, 4'-piperidine]-ethylene ketal maleate, m.p. 148-149°C. Analysis: Calculated for C30H30ClF2NO2S•C4H404: 62.05%C, 5.21%H, 2.13%N. Found: 61.94%C, 5.01%H, 2.16%N. Example 64 8.21 g (15.15 millimoles) of the free base 3-(4-chloro-•phenyl)-1-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydrospiro -[benzo(c)thiophene-1,4'-piperidine]-ethylene ketal from Example 63

i 62 ml varm 95% etanol ble tilsatt.31 ml 3N saltsyre i langsomt tempo til man fikk en suspensjon. Suspensjonen ble rørt'ved romtemperatur i' 3 timer og på et dampbad i 4 5 timer. Reaksjonsblandingen ble så fortynnet med 400 ml vann og gjort basisk med ammoniumhydroksyd." Den vandige blandingen ble ekstrahert med to 150 ml porsjoner av eter og to 250 ml porsjoner av en 1:1 eter:toluenblanding. De samlede organiske lag ble vasket med vann og en mettet vandig natriumkloridoppløsning og så tørket over magnesiumsulfat til en brun olje. Denne oljen ble kromatografert på silisiumdioksydgel med eter som elueringsmiddel og ga deretter et fast stoff. En del av produktet ble omkrystallisert tre ganger fra eter-pentan og ga 3-(4-klorfenyl)-1'-[3-(2,4-difluorbenzoy1)propyl]-l,3-dihydro-spiro- [benzo(c)thiofen-1,4'-piperidin], smp. 98-100°C. Analyse: Beregnet for C2gH26ClF2NOS: 67,52%C, 5,26%H, 2,81%N. in 62 ml of hot 95% ethanol was added.31 ml of 3N hydrochloric acid at a slow pace until a suspension was obtained. The suspension was stirred at room temperature for 3 hours and on a steam bath for 45 hours. The reaction mixture was then diluted with 400 mL of water and basified with ammonium hydroxide." The aqueous mixture was extracted with two 150 mL portions of ether and two 250 mL portions of a 1:1 ether:toluene mixture. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate to a brown oil. This oil was chromatographed on silica gel eluting with ether to give a solid. A portion of the product was recrystallized three times from ether-pentane to give 3-(4- chlorophenyl)-1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydro-spiro-[benzo(c)thiophene-1,4'-piperidine], mp 98-100°C. Analysis: Calculated for C2gH26ClF2NOS: 67.52%C, 5.26%H, 2.81%N.

Funnet: 67,25%C, 5,49%H, 2,69%N. Found: 67.25%C, 5.49%H, 2.69%N.

Eksempel 65Example 65

En blanding av 1,3-dihydro-3-fenylspiro-[benzo(c)thiofen-1 , 4 1 -piperidin ] fra eksempel 4 (3,75 g), 3,7 g y-klor-2,4-difluorbutyrofenonetylenketal, '2,5 g Kl og 4,0 g natriumbikarbonat i en blanding av 20 ml DMF og 20 ml 2-butanon ble kokt under tilbakeløp i 3 timer. Den avkjølte blandingen ble fortynnet med vann, ekstrahert tre ganger med eter og så vasket, hvoretter den tørkede eteroppløsningen ble konsentrert til et oljeaktig residum. Dette ble. renset ved gjennomgang i en aluminiumoksydkolonne.. Eluering med eter gir et tertiært amin som så ble omdannet til et krystallinsk maleat av 1'-[3-(2,4-difluorbenzoy1)propyl]-!,3-dihydro-3-fenylspiro- A mixture of 1,3-dihydro-3-phenylspiro-[benzo(c)thiophene-1,41-piperidine] from Example 4 (3.75 g), 3.7 g of γ-chloro-2,4-difluorobutyrophenoneethylene ketal , '2.5 g Kl and 4.0 g sodium bicarbonate in a mixture of 20 ml DMF and 20 ml 2-butanone were refluxed for 3 hours. The cooled mixture was diluted with water, extracted three times with ether and then washed, after which the dried ether solution was concentrated to an oily residue. This was. purified by passing through an alumina column. Elution with ether gives a tertiary amine which was then converted to a crystalline maleate of 1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro-

[benzo (c) thiof en-1, 4 1 -piperidin ]-etylenketalmaleat,- smp. 171-172,5°C. [benzo (c)thiophene-1,41-piperidine]-ethylene ketal maleate, m.p. 171-172.5°C.

Analyse:Analysis:

Beregnet for c30H3iF2NO2S'C4H4°4: 65'47%C' 5,66%H, 5,14%S. Funnet: 65,21%C, 5,68%H, 5,36%S. Calculated for c30H3iF2NO2S'C4H4°4: 65'47%C' 5.66%H, 5.14%S. Found: 65.21%C, 5.68%H, 5.36%S.

Eksempel 6 6Example 6 6

En oppløsning av 5,0 g av den frie basen l'-[3-(2,4-difluorbenzoy1)propyl]-l,3-dihydro-3-fenylspiro-[benzo(c)-thiofen-1,4'-piperidin]-etylenketal fra eksempel 65 i 20 ml 3N HC1 og 20 ml vann ble hensatt ved romtemperatur i 3 timer. Overskuddet av syre og oppløsningsmidler'ble fjernet under vakuum ved 60°C, og residumet ble gjort basisk med konsentrert NH^OH. Den.frigjorte oljen ble oppløst i eter, vasket og tør- A solution of 5.0 g of the free base 1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro-[benzo(c)-thiophene-1,4'- piperidine]-ethylene ketal from Example 65 in 20 mL 3N HCl and 20 mL water was allowed to stand at room temperature for 3 hours. The excess acid and solvents were removed under vacuum at 60°C, and the residue was made basic with concentrated NH 4 OH. The released oil was dissolved in ether, washed and dried

ket. Fjerning av oppløsningsmidlet gir en klar olje som ble omdannet, til et krystallinsk maleat i eter av l'-[3-(2,4-difluorbenzoyl)propyl]-l,3-dihydro-3-fenylspiro-[benzo(c)-.thiofen-1,4'-piperidin]-maleat, smp. 134-135°C. ket. Removal of the solvent afforded a clear oil which was converted to a crystalline maleate in ether of 1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro-[benzo(c)- .thiophene-1,4'-piperidine]-maleate, m.p. 134-135°C.

Analyse: Beregnet for<C>2gH27F2NOS•C4H404:66,67%C, 5,39%H, 5,53%S. Analysis: Calculated for<C>2gH27F2NOS•C4H4O4: 66.67%C, 5.39%H, 5.53%S.

Funnet: 66,21%C, 5,36%H, 5,79%S. Eksempel 67 Found: 66.21%C, 5.36%H, 5.79%S. Example 67

5,60 g av den frie basen 1<1->[3-(4-fluorbenzoyl)-propyl]-3-(3-metylfeny1)-1,3-dihydrospiro-[benzo(c)thiofen-1,4'-piperidin ]-etylenketal fra eksempel 50 i 56 ml varm etanol ble langsomt tilsatt 56 ml 3N saltsyre. Blandingen ble så kokt under.tilbakeløp i 45 minutter, avkjølt til romtemperatur, 5.60 g of the free base 1<1->[3-(4-fluorobenzoyl)-propyl]-3-(3-methylphenyl)-1,3-dihydrospiro-[benzo(c)thiophene-1,4' -piperidine]-ethylene ketal from Example 50 in 56 ml of hot ethanol was slowly added to 56 ml of 3N hydrochloric acid. The mixture was then refluxed for 45 minutes, cooled to room temperature,

gjort basisk med en liten mengde 40% natriumhydroksyd og så fortynnet med 350 ml vann. Oppløsningen ble ekstrahert med tre 150 ml porsjoner av diklormetan. De samlede diklormetanekstrak- made basic with a small amount of 40% sodium hydroxide and then diluted with 350 ml of water. The solution was extracted with three 150 mL portions of dichloromethane. The combined dichloromethane extracts

ter ble vasket med to 200 ml porsjoner med vann, en 75 ml por-were washed with two 200 ml portions of water, a 75 ml portion

sjon av natriumkloridoppløsning og så tørket over magnesium-tion of sodium chloride solution and then dried over magnesium

sulfåt til en olje. Denne ble oppløst i eter, filtrert og behandlet med eterholdig hydrogenbromid til et salt. Saltet ble vasket med eter og omkrystallisert fra metanol-aceton-eter til et pulver av 1'-[3-(4-fluorbenzoy1)propy1-1,3-dihydro-3-(3-mety1fenyl)spiro-[benzo(c)bhiofen-1,4'-piperidin]-hydrobromid som krymper til en gel ved .190-19 5°C og smelter, til en mørk væske ved 217-218°C. sulfate to an oil. This was dissolved in ether, filtered and treated with ethereal hydrogen bromide to form a salt. The salt was washed with ether and recrystallized from methanol-acetone-ether to give a powder of 1'-[3-(4-fluorobenzoyl)propyl-1,3-dihydro-3-(3-methylphenyl)spiro-[benzo(c) biophene-1,4'-piperidine] hydrobromide which shrinks to a gel at .190-195°C and melts to a dark liquid at 217-218°C.

Analyse:Analysis:

Beregnet for C29H3QFNOS•HBr: 64,44%C, 5,78%H, 2,59%N, 3,52%F. Funnet: 64,30%C, 5,-79%H, 2,48%N, 3,56%F. Calculated for C29H3QFNOS•HBr: 64.44%C, 5.78%H, 2.59%N, 3.52%F. Found: 64.30%C, 5.-79%H, 2.48%N, 3.56%F.

Claims (8)

1. Kjemisk forbindelse, karakterisert ved formelen1. Chemical compound, characterized by the formula eller en optisk isomer av en slik forbindelse eller et farma- - søytisk akseptabelt salt av en slik forbindelse, hvor R er hydrogen, hydroksy, benzoyloksy, laverealkyl, cykloalkyllaverealkyl eller cykloalkyllaverealkanoy1 og hvor cykloalkyIdelen kan inneholde fra 3-6 karbonatomer, laverealkenyl, fenylalkyl, difenylalkyl, difenylmetoksyalkyl, fenoksyalkyl, alkanoyl med fra.2-6 karbonatomer, fenylalkanoy1, benzoyl, benzoylalkyl, fenylhydroksyalky1, alkoksykarbony1 med fra 2-6 karbonatomer, fenoksykarbony1, cykloalkyIkarbonyl med fra 4-8 karbonatomer or an optical isomer of such a compound or a pharmaceutically acceptable salt of such a compound, where R is hydrogen, hydroxy, benzoyloxy, loweralkyl, cycloalkylloweralkyl or cycloalkylloweralkanoy1 and where the cycloalkyl part may contain from 3-6 carbon atoms, loweralkenyl, phenylalkyl, diphenylalkyl, diphenylmethoxyalkyl, phenoxyalkyl, alkanoyl with from 2-6 carbon atoms, phenylalkanoy1, benzoyl, benzoylalkyl, phenylhydroxyalkyl1, alkoxycarbonyl1 with from 2-6 carbon atoms, phenoxycarbonyl1, cycloalkylcarbonyl with from 4-8 carbon atoms de samme eller forskjellige og hver kan være hydrogen, laverealkyl, laverealkoksy, tri fluormety1, klor, brom, fluor, hydroksy-metylendioksy eller laverealky lthio-, m, n og n' er tall fra 1 til 3, og hvor summen av n og n' er 3 eller 4. the same or different and each can be hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, chlorine, bromine, fluorine, hydroxy-methylenedioxy or lower alkyl lthio-, m, n and n' are numbers from 1 to 3, and where the sum of n and n' is 3 or 4. 2'. Forbindelse ifølge krav 1, karakterisert ved at n og n <1> begge er 2. 2'. Compound according to claim 1, characterized in that n and n <1> are both 2. 3. Forbindelse ifølge krav 1, karakterisert ved R er hydrogen, alkyl med fra 1 til 3 karbonatomer, cykloalkyllaverealky1 eller cykloalkyllaverealkanoy1 hvor cykloalkyIdelen har fra 3 til 6 karbonatomer, fenyllaverealkyl, benzoyllaverealkyl, laverealkanoy1, fenoksykarbony1 \» / i 2 12 eller CH„) -C-PhR R , og hvor R og R er de samme eller forskjellige og hver kan være hydrogen-, alkyl eller alkoksy med fra 1 til 3 karbonatomer, klor, fluor, brom, trifluormetyl eller hydroksy. 3. Compound according to claim 1, characterized by R being hydrogen, alkyl with from 1 to 3 carbon atoms, cycloalkylloweralkyl1 or cycloalkylloweralkanoy1 where the cycloalkyl part has from 3 to 6 carbon atoms, phenylloweralkyl, benzoylloweralkyl, loweralkanoy1, phenoxycarbony1 \» / i 2 12 or CH„) -C-PhR R , and where R and R are the same or different and each can be hydrogen, alkyl or alkoxy with from 1 to 3 carbon atoms, chlorine, fluorine, bromine, trifluoromethyl or hydroxy. 4. ' Forbindelse ifølge krav 3, karakterisert v e d at n og n <1> begge er 2. 4. ' Compound according to claim 3, characterized in that n and n <1> are both 2. 5. Forbindelse ifø lgekrav 4, karakterisert ved at R er hydrogen, metyl, cyklopropylmety1, 4-fluor-benzoy lpropyl, eller'4-fluorbenzoylpropyl-etylenketal. 5. Compound according to claim 4, characterized in that R is hydrogen, methyl, cyclopropylmethyl, 4-fluoro-benzoylpropyl, or 4-fluorobenzoylpropyl-ethylene ketal. 6. Forbindelse ifølge krav 4, karakterisert v e.d at R er hydrogen, metyl eller fluorbenzoylpropyl og m er 1 eller 2. 6. Compound according to claim 4, characterized in that R is hydrogen, methyl or fluorobenzoylpropyl and m is 1 or 2. 7. Farmasøytisk preparat som kan brukes for behandling av depresjoner, karakterisert ved .å inneholde fra 0,5 til ca. 70 vekt-% av en forbindelse ifølge krav 1 samt et farmasøytisk akseptabelt fortynningsmiddel eller bærestoff. 7. Pharmaceutical preparation that can be used for the treatment of depression, characterized by containing from 0.5 to approx. 70% by weight of a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier. 8. Farmasøytisk preparat som kan'brukes som beroligende middel, karakterisert ved å inneholde fra 0,5 til ca. 70 vekt-% av en forbindelse ifølge krav 1 samt et farmasøytisk akseptabelt fortynningsmiddel eller bærestoff. 9.. Fremgangsmåte for fremstilling av forbindelser med formel I 8. Pharmaceutical preparation which can be used as a sedative, characterized by containing from 0.5 to approx. 70% by weight of a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier. 9.. Process for the preparation of compounds of formula I eller en optisk isomer forbindelse av en slik forbindelse eller et farmasøytisk akseptabelt salt av en slik forbindelse, hvor R er hydrogen, hydroksy, benzoyloksy, laverealkyl, cyklo-alky llaverealkyl eller cykloalkyllaveréalkanoyl hvor cyklo-alkyldelen kan ha fra 3 til 6 karbonatomer, laverealkeny1, fenylalkyl, difenylalkyl, difenylmetoksyalkyl, fenoksyalky1, alkanoyl med fra 2 til 6 karbonatomer, fenylalkanoyl, benzoyl, benzoylalky1, fenylhydroksyalkyl, alkoksykarbony1 med fra 2 til 6 karbonatomer, fenoksykarbony1, cykloalkylkarbonyl med fra 4 til 8 karbonatomer eller hvor Ph er -(CH„) - C-PhR <1> R <2> 12 ' fenyl; R og R er de samme eller forskjellige og hverkan være hydrogen, laverealkyl, laverealkoksy, trifluormetyl, klor, brom, fluor, hydroksy, metylendioksy eller laverealkylthio, m, n og n' er tall fra 1 til 3 og summen av n og n' er 3 eller 4, karakterisert ved at man:a) omdanner et 2-brom-fluorbenzen med formelen: or an optically isomeric compound of such a compound or a pharmaceutically acceptable salt of such a compound, where R is hydrogen, hydroxy, benzoyloxy, loweralkyl, cycloalkylloweralkyl or cycloalkylloweralkanoyl where the cycloalkyl part can have from 3 to 6 carbon atoms, loweralkeny1, phenylalkyl, diphenylalkyl, diphenylmethoxyalkyl, phenoxyalkyl1, alkanoyl with from 2 to 6 carbon atoms, phenylalkanoyl, benzoyl, benzoylalkyl1, phenylhydroxyalkyl, alkoxycarbonyl1 with from 2 to 6 carbon atoms, phenoxycarbonyl1, cycloalkylcarbonyl with from 4 to 8 carbon atoms or where Ph is -(CH„)-C-PhR <1> R <2> 12' phenyl; R and R are the same or different and each can be hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, chlorine, bromine, fluorine, hydroxy, methylenedioxy or lower alkylthio, m, n and n' are numbers from 1 to 3 and the sum of n and n' is 3 or 4, characterized by: a) converting a 2-bromo-fluorobenzene with the formula: til dets 2-litiumderivat med et laverealkyllitium ved temperaturer fra -80 til -20°C i et egnet oppløsningsmiddel så som eter, heksan eller tetrahydrofuran,b) reagerer 2-litiumderivatet med et cykloazalkanon med føl-gende formel: to its 2-lithium derivative with a lower alkyllithium at temperatures from -80 to -20°C in a suitable solvent such as ether, hexane or tetrahydrofuran, b) the 2-lithium derivative reacts with a cycloazalkanone of the following formula: hvor R er laverealkyl eller fenyllaverealkyl slik at man fremstiller en fenylcykloazalkanol med.formelen: where R is lower alkyl or phenyl lower alkyl so that a phenylcycloazalkanol is prepared with the formula: c) reagerer fenylcykloazalkanol med.en benzylmerkaptan med formelen: c) reacts phenylcycloazalkanol with.a benzyl mercaptan with the formula: i nærvær av en Lewis-syre ved temperaturer fra romtemperatur til 100°C slik at man fremstiller en 4-benzylthio-4-fenylcyklo- azalkan med formelen in the presence of a Lewis acid at temperatures from room temp to 100°C so that a 4-benzylthio-4-phenylcyclo- azalkan with the formula d) cykliserer nevnte 4-benzylthio-4-fenylcykloazalkan, e) eventuelt behandler én forbindelse med formel I hvor R er laverealkyl eller fenyllaverealkyl med et alkylklorformat eller fenylklorformat ved temperaturer fra 15 til 125°C med et egnet oppløsningsmiddel, hvorved man fremstiller en forbindelse med formelen d) cyclizes said 4-benzylthio-4-phenylcycloazalkane, e) optionally treating one compound of formula I where R is lower alkyl or phenyl lower alkyl with an alkyl chloroformate or phenyl chloroformate at temperatures from 15 to 125°C with a suitable solvent, thereby preparing a compound of the formula er som definert ovenfor, f) eventuelt behandler en forbindelse med formel I hvor R 3er is as defined above, f) optionally treats a compound of formula I where R is 3 med et basisk medium ved temperaturer fra 15°C til kokepunktet for reaksjonsblandingen, eller med et surt medium fra- 15 til 125°C slik at man får fremstilt en forbindelse med formel I hvor R er hydrogen,g) eventuelt behandler en forbindelse med formel I hvor R er hydrogen, med en forbindelse med formelen with a basic medium at temperatures from 15°C to the boiling point of the reaction mixture, or with an acidic medium from 15 to 125°C so that a compound of formula I is produced where R is hydrogen, g) possibly treating a compound of formula In which R is hydrogen, with a compound of the formula hvor R 1, R 2., m, n, n' og summen av n og n' er som definert ovenfor, h) eventuelt underkaster forbindelsen fremstilt som beskrevet under trinn g) ovenfor, en hydrolyse slik at man fremstiller en forbindelse med følgende formel where R 1, R 2., m, n, n' and the sum of n and n' are as defined above, h) possibly subjecting the compound prepared as described under step g) above to a hydrolysis so as to prepare a compound with the following formula 12' hvor R , R , m, n,■n' og summen av n og n1 er som definert ovenfor, eller i) eventuelt reagerer en forbindelse med formel I hvor R er hydrogen, med et laverealkanoylklorid eller anhydrid, benzoylklorid eller anhydrid, fenyllaverealkanoylklorid, laverealkyl-halogenid, alkenylhalogenid, cyklolaverealkanoylhalogenid eller fenyllaverealkylhalogenid, hvorved man fremstiller en forbin-deise med formel I hvor R 1, R 2 , m, n, n <1> samt summen av n og n^ er som definert ovenfor, og R er laverealkanoy1, benzoyl, fenyllaverealkanoy1, laverealkylalkeny1, cykloalkylalkanoyl og fenyllaverealkyl, k) eventuelt reduserer en forbindelse med formel I hvor R er alkoksykarbony1, fenoksykarbony1, laverealkanoy1, benzoy1-fenyllaverealkanoy1, cykloalkyllaverealkanoy1 eller benzoyl- ■ laverealkyl, slik at man fremstiller en forbindelse med formel I hvor R er laverealkyl, cykloalkyllaverealkyl, fenyllaverealkyl 1 2 eller fenylhydroksylaverealky1, og hvor R , R , m, n og n' samt summen av n og n <1> er som definert ovenfor, og 1) eventuelt dealkylerer- en forbindelse med formel I som inneholder minst en laverealkoksygruppe eller en fenylring, slik at man fremstiller en forbindelse med formel I som inneholder 2 minst en hydroksygruppe eller en fenylring og hvor R , R , m, n, n <1> og summen av n og n <1> er som definert ovenfor.12' where R , R , m, n,■n' and the sum of n and n1 are as defined above, or i) optionally reacts a compound of formula I where R is hydrogen, with a lower alkanoyl chloride or anhydride, benzoyl chloride or anhydride, phenyl lower alkanoyl chloride, lower alkyl halide, alkenyl halide, cyclo lower alkanoyl halide or phenyl lower alkyl halide, thereby producing a compound of formula I where R 1, R 2 , m, n, n <1> as well as the sum of n and n^ are as defined above, and R is loweralkanoy1, benzoyl, phenylloweralkanoy1, loweralkylalkeny1, cycloalkylalkanoyl and phenylloweralkyl, k) optionally reduces a compound of formula I where R is alkoxycarbonyl1, phenoxycarbonyl1, loweralkanoy1, benzoyl1-phenylloweralkanoy1, cycloalkylloweralkanoy1 or benzoyl- ■ loweralkyl, so that one prepares a compound of formula I where R is loweralkyl, cycloalkylloweralkyl, phenylloweralkyl 1 2 or phenylhydroxylaverealalkyl1, and where R , R , m, n and n' as well as the sum of n and n <1> are as defined above, and 1) optionally dealkylates- a compound of formula I which contains at least one lower alkoxy group or a phenyl ring, so that a compound of formula I is prepared which contains 2 at least one hydroxy group or a phenyl ring and where R , R , m, n, n <1> and the sum of n and n <1> are as defined above.
NO784039A 1977-12-02 1978-12-01 SUBSTITUTED 1,3-DIHYDROSPIRO (BENZO (C) THIOFENER) NO784039L (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85717777A 1977-12-02 1977-12-02
US94890878A 1978-10-05 1978-10-05

Publications (1)

Publication Number Publication Date
NO784039L true NO784039L (en) 1979-06-06

Family

ID=27127396

Family Applications (1)

Application Number Title Priority Date Filing Date
NO784039A NO784039L (en) 1977-12-02 1978-12-01 SUBSTITUTED 1,3-DIHYDROSPIRO (BENZO (C) THIOFENER)

Country Status (15)

Country Link
EP (1) EP0002283B1 (en)
JP (1) JPS5498775A (en)
AT (1) AT371468B (en)
AU (1) AU522997B2 (en)
CA (1) CA1122985A (en)
DE (1) DE2862307D1 (en)
DK (1) DK547278A (en)
EG (1) EG13536A (en)
FI (1) FI783664A (en)
GR (1) GR74052B (en)
HU (1) HU179984B (en)
IL (1) IL56094A0 (en)
NO (1) NO784039L (en)
NZ (1) NZ189057A (en)
PT (1) PT68855A (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2498603A1 (en) * 1981-01-29 1982-07-30 Delalande Sa Spiro iso:benzofuran and iso:benzothiophene derivs. - with anticonvulsant and analgesic activities
FR2519636A2 (en) * 1982-01-14 1983-07-18 Delalande Sa Spiro iso:benzofuran and iso:benzothiophene derivs. - with anticonvulsant and analgesic activities
NZ243065A (en) * 1991-06-13 1995-07-26 Lundbeck & Co As H Piperidine derivatives and pharmaceutical compositions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3959475A (en) * 1973-12-12 1976-05-25 American Hoechst Corporation Substituted 1,3-dihydrospiro(isobenzofuran)s

Also Published As

Publication number Publication date
DE2862307D1 (en) 1983-09-29
PT68855A (en) 1978-12-01
EG13536A (en) 1981-12-31
JPS5498775A (en) 1979-08-03
EP0002283A1 (en) 1979-06-13
AT371468B (en) 1983-06-27
DK547278A (en) 1978-12-01
CA1122985A (en) 1982-05-04
NZ189057A (en) 1982-03-23
IL56094A0 (en) 1979-01-31
GR74052B (en) 1984-06-06
FI783664A (en) 1979-06-03
AU4207378A (en) 1979-06-07
EP0002283B1 (en) 1983-08-24
AU522997B2 (en) 1982-07-08
HU179984B (en) 1983-01-28
ATA860978A (en) 1982-11-15

Similar Documents

Publication Publication Date Title
US3014911A (en) Derivatives of dibenzo[a, e]cycloheptatriene
US3341538A (en) Certain 2, 6-methano-3-benzazocines
IE902706A1 (en) Spirocyclic Antipsychotic Agents
EP1931652A2 (en) Amido compounds and their use as pharmaceuticals
CA1246563A (en) 3-arylcarbonyl- and 3-cycloalkylcarbonyl-1-aminoalkyl- 1h-indoles useful as analgesics
US4110459A (en) Benzoylpiperidylalkylindoles in alleviating pain
CA1055945A (en) Pharmaceutical compositions and method of producing antipsychotic activity without extrapyramidal symptoms
CA1132988A (en) N-¬3-(4-fluorobenzoyl)propyl|spiro¬dihydro- benzofuranpiperidine and -pyrrolidine|s, derivatives thereof, process for their manufacture and their use as medicaments
US4800212A (en) Pyrrolidone-2 compounds and anti-hypertensive use thereof
US3320265A (en) 6-phenyl-1, 2, 3, 4, 5, 6-hexahydro-2, 6-methano-3-benzazocines
US4209625A (en) Spiro[indoline-3,4&#39;-piperidine]s
NO784039L (en) SUBSTITUTED 1,3-DIHYDROSPIRO (BENZO (C) THIOFENER)
US4409229A (en) Antidepressive and tranquilizing substituted 1,3-dihydrospiro[benzo(c)thiophene]s
US4524207A (en) Process for preparing substituted 1,3-dihydrospiro[benzo(c)thiophene]s
US4379933A (en) Process for preparing spiro[indoline-3,4&#39;-piperidine]s
US4307235A (en) Spiro[indoline-3,4&#39;-piperidine]s
PT93503A (en) PROCESS FOR THE PREPARATION OF QUINOLINIC DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4667039A (en) 11-substituted 5H,11H-pyrrolo(2,1-C) (1,4)benzoxazepines as antipsychotic and analgesic agents
US4345081A (en) Spiro[indoline-3,4&#39;-piperidine]s
EP0102034B1 (en) Spiro(2h-1,4-benzodioxepin-3(5h)4&#39;-piperidine and 3&#39;-pyrrolidino) compounds, a process for preparing the same and their use as medicaments
HU185633B (en) Process for preparing phenyl-quinolizidine derivatives
US4477667A (en) Spiro[indoline-3,4&#39;-piperidine]s and related compounds
US4408050A (en) Spiro(indoline-3,4&#39;-piperidine) and related compounds
US4379932A (en) Process for preparing spiro[indoline-3,4&#39;-piperidine]s
US4024265A (en) Benzo[5,6]cyclohepta[1,2-c]pyridines