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NO762085L - - Google Patents

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Publication number
NO762085L
NO762085L NO762085A NO762085A NO762085L NO 762085 L NO762085 L NO 762085L NO 762085 A NO762085 A NO 762085A NO 762085 A NO762085 A NO 762085A NO 762085 L NO762085 L NO 762085L
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Norway
Prior art keywords
compounds
methyl
formula
solution
water
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Application number
NO762085A
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Norwegian (no)
Inventor
J-M Bastian
Original Assignee
Sandoz Ag
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Publication date
Priority claimed from CH817475A external-priority patent/CH613204A5/en
Priority claimed from CH817375A external-priority patent/CH615927A5/en
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of NO762085L publication Critical patent/NO762085L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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

Description

"Fremgangsmåte for fremstilling av nye organiske forbindelser". "Procedure for the production of new organic compounds".

Foreliggende oppfinnelse vedrorer en fremgangsmåte for frem/ stilling av nye organiske forbindelser med formel I The present invention relates to a method for the production/preparation of new organic compounds with formula I

hvori in which

står for hydrogen eller alkyl med 1-4 karbonatomer ogstands for hydrogen or alkyl with 1-4 carbon atoms and

1*2 betyr alkyl med 1-4 karbonatomer, og deres syreaddisjonssalter. 1*2 means alkyl with 1-4 carbon atoms, and their acid addition salts.

Hvis substituenten R, står for i det foregående definert alkyl, utgjor den foretrukket metyl eller etyl. Foretrukket er substituenten R^ anordnet i 6- eller 7-, foretrukket i 7-stillingen av benzo(4, 5) cyklohepta(1, 2 - b) tiophenskjelettet og utgjor foretrukket metyl. If the substituent R stands for alkyl as defined above, it is preferably methyl or ethyl. Preferably, the substituent R is arranged in the 6- or 7-, preferably in the 7-position of the benzo(4, 5) cyclohepta(1, 2-b) thiophene skeleton and is preferably methyl.

Foretrukket er spesielt slike forbindelser med formel I hvori R^står for hydrogen eller metyl og R£ betyr metyl og er anordnet i 6- eller 7-stilling av ringskjelettet. Particularly preferred are such compounds of formula I in which R^ stands for hydrogen or methyl and R£ means methyl and is arranged in the 6- or 7-position of the ring skeleton.

Det særegne ved fremgangsmåten i henhold til oppfinnelsen for fremstilling av forbindelsene med formel I og deres syreaddisjonssalter er at The peculiarity of the process according to the invention for the preparation of the compounds of formula I and their acid addition salts is that

a) for fremstilling av forbindelser med formel Ia a) for the preparation of compounds of formula Ia

hvori R 2 har den ovennevnte betydning og R* betyr alkyl med 1-4 karbonatomer, avspaltes vann fra forbindelser med formel II hvori R^ og R2har den ovennevnte betydning, eller b) for fremstilling av forbindelser med formel Ib hvori har den ovennevnte betydning, avspaltes resten R_ fra forbindelser med formel III6/ in which R 2 has the above-mentioned meaning and R* means alkyl with 1-4 carbon atoms, water is split off from compounds of formula II in which R^ and R 2 have the above-mentioned meaning, or b) for the production of compounds of formula Ib in which it has the above-mentioned meaning, the residue R_ is cleaved from compounds of formula III6/

hvori R2har den ovennevnte betydning og R^betyr en avspaltbar rest, in which R2 has the above-mentioned meaning and R^ means a cleavable residue,

og de erholdte forbindelser med formel I overfores eventuelt i sine syreaddisjonssalter. and the obtained compounds of formula I are optionally transferred into their acid addition salts.

Vannavspaltingen fra forbindelsene med formel II i henhold til fremgangsmåten a) kan skje på for avspalting av vann fra analoge karbanalerei og for seg kjent måte, for eksempel ved innvirkning av egnede vannavspaltende midler, eventuelt i nærvær av et under reaksjonsbe tingel sene inert orjganisk losning- middel, for eksempel en lavere alkohol. Som vannavspaltende middel kan anvendes for eksempel mineralsyrer eller sterke organiske syrer eller også syreanhydrider eller halogenider. The separation of water from the compounds of formula II according to method a) can take place in a manner known per se for the separation of water from analogous carbanals, for example by the action of suitable water-releasing agents, possibly in the presence of an inert organic solution under the reaction conditions. medium, for example a lower alcohol. For example, mineral acids or strong organic acids or also acid anhydrides or halides can be used as water-releasing agents.

Avspaltingen av resten R 3 fra forbindelser med formel III etter fremgangsmåten b) kan skje etter for avspalting av aminobeskyttelsesgrupper fra heterocykliske aminer i og for seg vanlige metoder, for eksempel solvolytisk, spesielt hydro-lytisk eller også hydrogenolytisk. Egnede solvolytisk, spesielt avspaltbare beskyttelsesgrupper er for eksempel alkoksy- eller aryloksykarbonylgrupper, spesielt lavere alkoksykarbonylgrupper, eller nitrilgruppen. Den solvolytiske spalting av forbindelsene med formel III kan gjennomfores alt etter arten av resten R^ foretrukket i surt medium, for eksempel i nærvær av sterke mineralsyrer eller i alkalisk medium, for eksempel i nærvær av uorganiske baser. Egnede hydrogenolytisk avspaltbare beskyttelsesgrupper er for eksempel eventuelt substituerte The cleavage of the residue R 3 from compounds of formula III according to method b) can take place after cleavage of amino protecting groups from heterocyclic amines in per se common methods, for example solvolytically, especially hydrolytically or also hydrogenolytically. Suitable solvolytically, especially cleavable protecting groups are, for example, alkoxy or aryloxycarbonyl groups, especially lower alkoxycarbonyl groups, or the nitrile group. The solvolytic cleavage of the compounds of formula III can be carried out depending on the nature of the residue R 1 preferably in an acidic medium, for example in the presence of strong mineral acids or in an alkaline medium, for example in the presence of inorganic bases. Suitable hydrogenolytically cleavable protecting groups are, for example, optionally substituted

benzylgrupper. Avspaltingen med hydrogenolyse kan skje påbenzyl groups. The cleavage with hydrogenolysis can take place on

i og for seg kjent måte, for eksempel ved hjelp av katalytisk hydrogenering i nærvær av platina- eller palladium-katalysatorer. in a manner known per se, for example by means of catalytic hydrogenation in the presence of platinum or palladium catalysts.

De ved fremgangsmåten i henhold til oppfinnelsen fremstillbare forbindelser med formel I kan foreligge i form av de fri baser eller deres syreaddisjonssalter. De fri baser kan på i og for seg kjent måte overfores i sine syreaddisjonssalter og omvendt. Således kan forbindelsene med formel I for eksempel med uorganiske syrer som saltsyre eller med organiske syrer som for eksempel fumarsyre danne syreaddisjonssalter. The compounds of formula I which can be prepared by the method according to the invention can be in the form of the free bases or their acid addition salts. The free bases can be converted in a manner known per se into their acid addition salts and vice versa. Thus, the compounds of formula I can, for example, form acid addition salts with inorganic acids such as hydrochloric acid or with organic acids such as fumaric acid.

Utgangsforbindelsene kan erholdes på fSigende måte:The output connections can be obtained in the following way:

a') Forbindelser med formel II kan for eksempel fremstilles ved at et keton med formel IV a') Compounds of formula II can, for example, be prepared by a ketone of formula IV

hvori har den ovennevnte betydning, omsettes med en Grignard-forbindelse med formel V wherein it has the above meaning, is reacted with a Grignard compound of formula V

hvori R<*>har den ovennevnrte betydning og X står for klor, brom eller jod og det erholdte kompleks hydrolyseres. b<1>) Forbindelser med formel III kan for eksempel erholdes ved at ketoner med formel IV omsettes med en Grignard-forbindelse med formel in which R<*> has the above meaning and X stands for chlorine, bromine or iodine and the resulting complex is hydrolysed. b<1>) Compounds of formula III can be obtained, for example in that ketones of formula IV are reacted with a Grignard compound of formula

hvori X har den ovennevnte betydning og R^ betyr metyl eller en hydrogenolytisk avspaltbar rest, det erholdte kompleks hydrolyseres, fra reaksjonsproduktet avspaltes vann analogt med fremgangsmåten a) og deretter overfores en mulig forekommende metylgruppe R^på i og for seg kjent måte, for eksempel ved omsetning med klormaursyreestere eller med bromcyan, i en solvolytisk avspaltbar gruppe. in which X has the above meaning and R^ means methyl or a hydrogenolytically cleavable residue, the resulting complex is hydrolyzed, water is removed from the reaction product analogously to method a) and then a possible methyl group is transferred to R^ in a manner known per se, for example by reaction with chloroformate esters or with cyanogen bromide, in a solvolytically cleavable group.

I deri .utstrekning fremstillingen av utgangsforbindelsene ikkeTo that extent the production of the output compounds does not

er beskrevet, er disse kjente eller kan fremstilles etter i og for seg kjente metoder henholdsvis analogt med de her beskrevede eller analogt med i og for seg kjente metoder. are described, these are known or can be produced according to per se known methods, respectively analogous to those described here or analogous to per se known methods.

Forbindelsene med formel I og deres physiologisk tålebare syreaddisjonssalter utmerker seg ved interessante farma-kologiske egenskaper og kan folgelig anvendes som medisin. The compounds of formula I and their physiologically tolerable acid addition salts are distinguished by interesting pharmacological properties and can consequently be used as medicine.

Spesielt har substansene sterkere utpregede analgetiske virkninger enn det kunne ventes for forbindelser av denne strukturtype, påvist ved standard-tester med dyr. For eksempel hemmer substansene i mus i dose på 0,5 - 20 mg/kg p.o. fenylbenzochinonsyndromet og er analgetisk virksomme i mus ved tail-flick-testen i dose på 3 - 50 mg/kg kropsvekt tilfort p.o. eller s.c. In particular, the substances have stronger pronounced analgesic effects than could be expected for compounds of this structural type, demonstrated in standard tests with animals. For example, the substances inhibit in mice in doses of 0.5 - 20 mg/kg p.o. the phenylbenzoquinone syndrome and are analgesically effective in mice in the tail-flick test at a dose of 3 - 50 mg/kg body weight added p.o. or s.c.

På grunn av deres analgetiske egenskaper kan forbindelsene anvendes for behandling av akutte eller kroniske smertetil-stander av forskjellig opphav. For smertebehandling kan alt etter arten av den tilstand som skal behandles, den anvendte substans og formen for dens tilfbrsel daglige dose på 10 - 100 mg være egnet. Due to their analgesic properties, the compounds can be used for the treatment of acute or chronic pain conditions of various origins. For pain treatment, depending on the nature of the condition to be treated, the substance used and the form of its administration, a daily dose of 10 - 100 mg may be suitable.

Videre har forbindelsene histaninolytiske såvel som serotomin-og acetylcholin-antagonistiske egenskaper, påvist ved standard-tester med dyr, for eksempel ved histamin-, serotonin- og acetylcholin-giftighetstester med marsvin i doser på 0,1 - Furthermore, the compounds have histaninolytic as well as serotomin- and acetylcholine-antagonistic properties, demonstrated in standard tests with animals, for example in histamine, serotonin and acetylcholine toxicity tests with guinea pigs in doses of 0.1 -

20 mg/kg kroppsvekt s.c.20 mg/kg body weight s.c.

På grunn av deres antagonistiske egenskaper overfor biogene aminer kan forbindelsene anvendes som antaminika, for eksempel som antihistaminica og for behandling av migrene. For dette kan alt etter arten av den tilstand som skal behandles, den anvendte substans og tilforselsmåten daglig dose på 10 100 mg være egnet. Due to their antagonistic properties towards biogenic amines, the compounds can be used as antiamines, for example as antihistaminics and for the treatment of migraine. For this, depending on the nature of the condition to be treated, the substance used and the method of administration, a daily dose of 10,100 mg may be suitable.

Som medisin kan forbindelsene med formel I og deres physiologisk tålbare syreaddisjonssalter inneholdes sammen med egnede farmasoytiske hjelpestoffer i for enteral, foretrukket oral, eller parenteral tilforsel egnede faste eller flytende galeniske preparater, om onsket med forsinket virkestoffav-givelse. Eksempler på slike preparater for enteral tilforsel er bl.annet pulver, granulater, tabletter, kapsler, drageer siruper, dråper, suppositorier etc. Som eksempel på preparater for parenteral tilforsel nevnes injeksjonslSsninger eller injiserbare vvandige eller oljeaktige suspensjoner. As medicine, the compounds of formula I and their physiologically tolerable acid addition salts can be contained together with suitable pharmaceutical excipients in solid or liquid galenic preparations suitable for enteral, preferably oral, or parenteral administration, if desired with delayed active ingredient release. Examples of such preparations for enteral administration include powders, granules, tablets, capsules, dragees, syrups, drops, suppositories, etc. Examples of preparations for parenteral administration include injection solutions or injectable aqueous or oily suspensions.

For oral tilforsel er for eksempel tabletter med 0,5, 1, 2, eller 5 mg virkestoff/dose egnet. For oral administration, for example, tablets with 0.5, 1, 2 or 5 mg of active ingredient/dose are suitable.

Fremstillingen av de galeniske preparater kan skje ved hjelp av innen den farmasøytiske teknikk i og for seg vanlige metoder under anvendelse av vanlige faste eller flytende bærer- og hjelpe-stoffer. Som faste bærestoffer kan anvendes physiologisk indifferente faststoffer som manhit, laktose, stivelse, organiske eller uorganiske kalsiumsalter, etc. The preparation of the galenic preparations can take place with the help of pharmaceutical technology in and of itself usual methods using usual solid or liquid carriers and auxiliary substances. Physiologically indifferent solids such as mannitol, lactose, starch, organic or inorganic calcium salts, etc. can be used as solid carriers.

Hvis det onskes en retardering av virkestoffavgivelsen,If a retardation of the release of the active substance is desired,

kan fyllstoffer som forsinker virkestoff-frisettingen tilsettes, som for aeksempel physiologisk noytrale polymerer som cellulosederivater eller syntetiske polymerer, fettalko-holer og andre voksaktige substanser. For suppositoriefrem-stilling Hkan det for dette formål anvendes vanlige substanser. Som flytende bærestoffer egner seg for eksempel vann, etanol eller physiologisk tålbare oljer. Videre kan preparatene tilsettes andre farmasoytisk vanlige hjelpestoffer, for eksempel tablettfyllstoffer som bindemidler, for eksempel polyvinylpyrrolidoner, tablettsprengmiddler, glidemidler, fillers that delay the release of the active ingredient can be added, such as, for example, physiologically neutral polymers such as cellulose derivatives or synthetic polymers, fatty alcohols and other waxy substances. For suppository production, ordinary substances can be used for this purpose. Suitable liquid carriers are, for example, water, ethanol or physiologically tolerable oils. Furthermore, the preparations can be added to other pharmaceutical common excipients, for example tablet fillers as binders, for example polyvinylpyrrolidones, tablet disintegrants, lubricants,

for eksempel magnesiumstearat, og videre konserveringsmidler, puffersubstanser, smakskorrigerende midler, etc. for example magnesium stearate, and further preservatives, buffer substances, taste correcting agents, etc.

I de etter f Sigende eksempler som skal illustre, "oppfinnelsen er alle temepraturangivelser i °C. In the following examples to illustrate the invention, all temperature indications are in °C.

EKSEMPEL 1 4-( 9, 10- dihydro- 7- metvl- 4H- benzo( 4, 5)-cvklohepta( 1, 2- b) tiophen- 4- yliden)- l-me tylpi per idin. EXAMPLE 1 4-(9,10-dihydro-7-methyl-4H-benzo(4,5)-cyclohepta(1,2-b)thiophen-4-ylidene)-1-methylpyridine.

En losning av 21,5 g 9,l0-dihydro-7-metyl-4-(l-metyl-4-piper-idyl)-4H-benzo(4,5) cyklohepta(1,2-b)tiophen-4-ol i 210 ml eddiksyreanhydrid oppvarmes til koking i 18 timer/inndampes under redusert trykk og resten uthelles på 1 liter isblandet vann. Den erholdte ISsning innstilles til pH 14 med natronlut, omrSres i 30 minutter ved romtemperatur og utrystes med metylen klorid. Ekstraktene vaskes noytral med vann, torkes over kaliumkarbonat, inndampes, den erholdte rest loses i 500 ml metyibenklorid og filtrers over 200 aluminiumoksyd med aktivitetstrinn II-III. Etter avdamping av losningsmidlet overfores den som rest tilbakeblivende i overskriften nevnte forbindelse i sitt fumarat i metanol og omkrystalliseres i gang. A solution of 21.5 g of 9,10-dihydro-7-methyl-4-(1-methyl-4-piperidyl)-4H-benzo(4,5)cyclohepta(1,2-b)thiophene-4 -ol in 210 ml of acetic anhydride is heated to boiling for 18 hours/evaporated under reduced pressure and the residue poured into 1 liter of ice-cold water. The obtained solution is adjusted to pH 14 with caustic soda, stirred for 30 minutes at room temperature and shaken out with methylene chloride. The extracts are washed neutrally with water, dried over potassium carbonate, evaporated, the residue obtained is dissolved in 500 ml of methylene chloride and filtered over 200 alumina with activity level II-III. After evaporation of the solvent, the residual compound mentioned in the title is transferred in its fumarate in methanol and recrystallized in progress.

Smeltepunkt: 200 - 201°C.Melting point: 200 - 201°C.

Utgangsmaterialet kan erholdes som folger:The starting material can be obtained as follows:

a) Til en kokende losning av 131 g 2,4-dimetylbenzonitril ia) To a boiling solution of 131 g of 2,4-dimethylbenzonitrile i

600 ml vannfri benzen tildr^fppes samtidig en løsning av 52 600 ml of anhydrous benzene is added at the same time to a solution of 52

.ml brom i 300 ml benzen og en losning av 5,0 g a, å*;-Azoiso-butyronitril i lopet av 40 minutter, reaksjonsblandingen .ml of bromine in 300 ml of benzene and a solution of 5.0 g of α,α*;-Azoiso-butyronitrile over the course of 40 minutes, the reaction mixture

omroressi 3,5 timer ved koketemperatur og videre i 12 timerstir for 3.5 hours at boiling temperature and continue for 12 hours

s. ved romtemperatur. Ved 70°C lar man nå 183 ml trietylphosphit tildryppe i lopet av 30 minutter under omroring, temperaturen forhoyes langsomt til 115 - 120 C hvorved det dannede pp. at room temperature. At 70°C, 183 ml of triethyl phosphite is now allowed to drip over the course of 30 minutes while stirring, the temperature is slowly raised to 115 - 120 C, whereby the formed

etylbromid avdestilleres med benzen, og det omrores videre ved denne temperatur i 3 timer. Reaksjonsblandingen frak-sjoneres under hoyvakuum hvorved blandingen av (2-cyan-5-metylbenzyl)- og (4-cyan-3-metylbenzyl )phosphonsyxe;dietyléstér går over ved 165 - 172°C/0,1 torr. ethyl bromide is distilled off with benzene, and it is stirred further at this temperature for 3 hours. The reaction mixture is fractionated under high vacuum whereby the mixture of (2-cyano-5-methylbenzyl)- and (4-cyano-3-methylbenzyl)phosphonic acid diethyl ester undergoes conversion at 165 - 172°C/0.1 torr.

b) Til en suspensjon av 37 g natriummetylat i 1100 ml N,N-'.. ; dimetylformamid lar man ved 35 - 40°C en losning av 157 g av b) To a suspension of 37 g of sodium methylate in 1100 ml of N,N-'.. ; dimethylformamide is left at 35 - 40°C to dissolve 157 g of

; , den ovennevnte isomerblanding og 65 g 2-tiophenaldehyd tildryppe i lopet av ca. 20 minutter, reaksjonsblandingen^omrores videre i 1 time ved 40°C, avkjoles til"20°C og uthelles ,på isblandet vann. De organiske, produkter uttrekkes med eter, ekstraktene vaskes med mettet kokesaltlosning, torkes over magnesiumsulfat og inndampes. De lettflyktige komponenter fjernes under hoyvakuum ved 100 - 110°C og blandingen av 4-metyl-2-(2-(2-tienyl)vinyl)benzonitril og 2-metyl-4(2-(2-tienyl)vinyl)benzonitril erholdes. Den 2-metylisomere skilles fra blandingen ved krystallisering fra etanol og det anrikede 4-metyl-2-(2-(2-tienyl)vinyl) benzonitril destilleres under hoyvakuum. ; , the above isomer mixture and 65 g of 2-thiophenaldehyde added dropwise over the course of approx. 20 minutes, the reaction mixture is stirred for 1 hour at 40°C, cooled to 20°C and poured into ice-cold water. The organic products are extracted with ether, the extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. components are removed under high vacuum at 100 - 110°C and the mixture of 4-methyl-2-(2-(2-thienyl)vinyl)benzonitrile and 2-methyl-4(2-(2-thienyl)vinyl)benzonitrile is obtained. 2-Methylisomers are separated from the mixture by crystallization from ethanol and the enriched 4-methyl-2-(2-(2-thienyl)vinyl)benzonitrile is distilled under high vacuum.

Kokepunkt 0,1 = 210;;- 220°Boiling point 0.1 = 210;;- 220°

c) En blanding av 45 g av det ovennevte destilat i 500 ml vannfri etanol "hydrogeneres i nærvær av 15 g 5% palladium c) A mixture of 45 g of the above distillate in 500 ml of anhydrous ethanol is "hydrogenated in the presence of 15 g of 5% palladium

på kull ved 100°C og 25 ato i 24 timer. Etter klar-filtrering og inndamping av filtratet videreforarbeides hydrogeneringsproduktet, 4-metyl-2-(2-tienyl)etyl)benzonitril som er forurenset med litt 2-metyl-4-(2-(2-tienyl) etylbenzonitril uten rensing. on charcoal at 100°C and 25 ato for 24 hours. After clear filtration and evaporation of the filtrate, the hydrogenation product, 4-methyl-2-(2-thienyl)ethyl)benzonitrile, which is contaminated with a little 2-methyl-4-(2-(2-thienyl)ethylbenzonitrile, is further processed without purification.

d) Til en losning av 74 g kaliumhydroksyd i 200 ml dietylen-glykol-monoetyleter ;> tildryppes ved 180°C i lopet av 30 d) To a solution of 74 g of potassium hydroxide in 200 ml of diethylene glycol monoethyl ether;> is added dropwise at 180°C over the course of 30

minutter en losning av 38 g av det ovennesmte produkt i 50 ml dietylenglykolmonoetyleter. Reaksjonsblandingen minutes a solution of 38 g of the above product in 50 ml of diethylene glycol monoethyl ether. The reaction mixture

omrores videre i 3 timer ved den samme temperatur, avkjoles til 100°C, uthelles på 1 liter vann og den erholdte losning (etter avkjoling til romtemperatur) utvaskes med eter. Den vandige losning innstilles nå under avkjoling med 4 N svovelsyre til pH 1 og utrystes flere ganger med eter. Ekstraktene vaskes med vann, torkes over magnesiumsulfat og inndampes. Resten loses i 1 liter metylenklorid filtreres gjennom silikagel og inndampes. Fra inndampings-resten krystalliserer 4-metyl-2-(2-(2-tienyl)etyl)benzo-syre fra. eter/petroleter. stirred further for 3 hours at the same temperature, cooled to 100°C, poured into 1 liter of water and the solution obtained (after cooling to room temperature) washed out with ether. The aqueous solution is now adjusted under cooling with 4 N sulfuric acid to pH 1 and shaken several times with ether. The extracts are washed with water, dried over magnesium sulphate and evaporated. The residue is dissolved in 1 liter of methylene chloride, filtered through silica gel and evaporated. From the evaporation residue, 4-methyl-2-(2-(2-thienyl)ethyl)benzoic acid crystallizes from. ether/petroleum ether.

Smeltepunkt 75 - 78°C (svaktforurenset med 2-metyl-4-(2-(2-tienyl)etyl)benzosyre. Melting point 75 - 78°C (slightly contaminated with 2-methyl-4-(2-(2-thienyl)ethyl)benzoic acid.

e) En blanding av 22 g 4-metyl-2-(2-(2-tienyl)-etyl)benzo-syre og 110 g polyfosforsyre omrores i 20 minutter ved e) A mixture of 22 g of 4-methyl-2-(2-(2-thienyl)-ethyl)benzoic acid and 110 g of polyphosphoric acid is stirred for 20 minutes at

90°C, avkjoles, uthelles på 300 ml vann og utrystes flere ganger med eter. De eteriske losninger vaskes med vann, med 5% ammoniakklosning og på nytt med vann," torkes så over magnesiumsulfat og inndampes. Resten renses ved kolonnekromatografering over 600 g noytralt aluminiumoksyd (aktivitetstrinn II-III) under anvendelse av metylenklorid som elueringsmiddel og det erholdte 9,10-dihyro-7-metyl-4H benzo(4,5)cyklohepta(l,2-b)tiophen-4-on videreforarbeides uten rensing. 90°C, cooled, poured into 300 ml of water and shaken several times with ether. The ethereal solutions are washed with water, with 5% ammonia solution and again with water," then dried over magnesium sulfate and evaporated. The residue is purified by column chromatography over 600 g of neutral alumina (activity level II-III) using methylene chloride as eluent and the obtained 9 ,10-dihydro-7-methyl-4H benzo(4,5)cyclohepta(1,2-b)thiophen-4-one is further processed without purification.

f) 3,1 g magnesiumspon overhelles med 10 ml vannfritt tetrahydrofuran, anetses med jod og 1 - 2 dråper etylenbromid f) 3.1 g magnesium shavings are poured over with 10 ml anhydrous tetrahydrofuran, annealed with iodine and 1 - 2 drops of ethylene bromide

og etter at reaksjonen er begynt tilsettes en losning av 17,4 g 4-klor-l-metylpiperidin i 70 ml vannfritt tetra-"hydrofuran dråpevis slik at reaksjonen holdes i gang. Etter tildryppingen omrores reaksjonsblandingen i 2 timer ved koketemperatur, avkjoles til 20°C og tilsettes ved denne temperatur en losning av 15,6 9,10-dihydro-7-metyl-4H-benzo-(4,5) cyklohepta (1,2-b)tiophen-4-on i 60 ml vannfritt tetrahydrofuran dråpevis. Reaksjonsblandingen omrores nå and after the reaction has started, a solution of 17.4 g of 4-chloro-1-methylpiperidine in 70 ml of anhydrous tetrahydrofuran is added dropwise so that the reaction is kept going. After the addition, the reaction mixture is stirred for 2 hours at boiling temperature, cooled to 20 °C and at this temperature a solution of 15,6 9,10-dihydro-7-methyl-4H-benzo-(4,5)cyclohepta (1,2-b)thiophen-4-one in 60 ml of anhydrous tetrahydrofuran is added The reaction mixture is now stirred

i 2 timer/ / ved romtemperatur, uthelles på 300 ml 20% ammoniumkloridlosning og hele blandingen utrystes flere ganger med eter. De eteriske losninger vaskes med vann, torkes over kaliumkarbonat og inndampes. Den som fast rest tilbakeblivende 9,10-dihydro-7-metyl-4-(l-metyl-4-piperidyl-^-4H-benzo (4, 5 )-cyklohepta (1, 2-b) tiophen-4-ol omkrystalliseres fra eter/petroleter. for 2 hours/ / at room temperature, 20% ammonium chloride solution is poured onto 300 ml and the entire mixture is shaken several times with ether. The ether solutions are washed with water, dried over potassium carbonate and evaporated. The solid residue remaining 9,10-dihydro-7-methyl-4-(1-methyl-4-piperidyl-^-4H-benzo (4, 5 )-cyclohepta (1, 2-b) thiophen-4-ol recrystallized from ether/petroleum ether.

Smeltepunkt: 151 - 154°C (sintring fra 147°C).Melting point: 151 - 154°C (sintering from 147°C).

Analogt med eksempel 1 kan også de følgende 4r(9,10-dihydro-4H benzo(4,5)cyklohepta (1,2-b)tiophen-4-yliden)-l-alkylpiperidin-derivater erholdes fra tilsvarende 9,lO-dihydro-4-(l-aikyl-4-piperidyl)-4H-benzo(4,5)cyklohepta(1,2-b)tiophen-4-ol-forbind eiser: Analogous to example 1, the following 4r(9,10-dihydro-4H benzo(4,5)cyclohepta (1,2-b)thiophen-4-ylidene)-1-alkylpiperidine derivatives can also be obtained from the corresponding 9,10- Dihydro-4-(1-alkyl-4-piperidyl)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4-ol compound:

EKSEMPEL_2 4-( 9, lO- dihydro- 7- metvl- 4H- benzo( 4, 5) EXAMPLE_2 4-(9,10-dihydro-7-methyl-4H-benzo(4,5)

cyklohepta ( 1, 24»b) tiophen- 4- yliden ) piper-cyclohepta (1, 24»b) thiophen- 4-ylidene) piper-

idin id

20 g rå 4-(9,lO-dihydro-7-metyl-4H-benzo(4,5)-cyklohepta(1,2-b)tiopheh-4-ylidén)-l-piperidinkarboksylsyreetylester opptas i 250 ml 48% bromhydrogensyre og oppvarmes til koking i 30 20 g of crude 4-(9,10-dihydro-7-methyl-4H-benzo(4,5)-cyclohepta(1,2-b)thiopheh-4-ylidene)-1-piperidinecarboxylic acid ethyl ester are taken up in 250 ml of 48% hydrobromic acid and heated to boiling for 30

minutter. Etter avkjoling fortynnes reaksjonslosningen med vann, innstilles alkalisk med konsentrert natronlut og ekstraheres med metylenklorid. Den organiske losning vaskes med vann, torkes over natriumsulfat og inndampes. Den som rest tilbakeblivende i overskriften nevnte forbindelse overfores i hydrogenfumaratet. minutes. After cooling, the reaction solution is diluted with water, made alkaline with concentrated caustic soda and extracted with methylene chloride. The organic solution is washed with water, dried over sodium sulphate and evaporated. The remaining compound mentioned in the title is transferred into the hydrogen fumarate.

Smeltepunkt: Spalting fra 210°C (etanol).Melting point: Decomposition from 210°C (ethanol).

Utgangsmaterialet kan fremstilles som folger:The starting material can be produced as follows:

Til en til 40°C forvarmet losning av 5,9 g 4-(9,10-dihydro-7-metyl-4H-benzo(4,5)cyklohepta(I,2-b) tiophen-4-yliden)-1-metylpiperidin i 150 ml vannfri benzen tildryppes i lopet av 30 minutter en losning av 8,0 g klormaursyreetylester i 30 ml vannfri benzen, reaksjonsblandingen omrores i en time ved den samme temperatur og i 3 timer ved koketemperaturen, avkjoles til romtemperatur og utvaskes med 0,5 N saltsyre og med vann. Benzenlosningen torkes så over natriumsulfat og inndampes og den som rest tilbakeblivende 4-(9,l0-dihydro-7-metyl-4H-benzo(4,5)cyklohepta(1,2-b)tiophen-4-yliden)-l-piperidinkarboksylsyreetylester videreforarbeides i rå tilstand. To a preheated to 40°C solution of 5.9 g of 4-(9,10-dihydro-7-methyl-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4-ylidene)-1 -methylpiperidine in 150 ml of anhydrous benzene is added dropwise over the course of 30 minutes to a solution of 8.0 g of chloroformate ethyl ester in 30 ml of anhydrous benzene, the reaction mixture is stirred for one hour at the same temperature and for 3 hours at the boiling temperature, cooled to room temperature and washed out with 0 .5 N hydrochloric acid and with water. The benzene solution is then dried over sodium sulfate and evaporated and the remaining 4-(9,10-dihydro-7-methyl-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4-ylidene)-1- Piperidine carboxylic acid ethyl ester is further processed in the crude state.

EKSEMPEL_PÅ_ANVEITOELSEN_ 44( 9, 10- dihydro- 7- metvl- 4H- benzo ( 4, 5)- cyklohepta( 1, 2- b) tiophen- 4 yliden)- l- metylpiperidin- holdiqe kapsJber EXAMPLE_OF_THE_USE_44(9,10-dihydro-7-methyl-4H-benzo(4,5)-cyclohepta(1,2-b)thiophen-4ylidene)-1-methylpiperidine-holdiqe caps

Sammensetning:Composition:

Substansene blandes sammen og innfylles i hård-gelantin-kapsler. The substances are mixed together and filled into hard gelatin capsules.

PATENTKRAVPATENT CLAIMS

Fremgangsmåte for fremstilling av nye forbindelser ,med formel Procedure for the production of new compounds, with formula

I IN

hvori in which

står for hydrogen eller alkyl med 1-4 karbonatomer og R2betyr alkyl med 1-4 karbonatomer, stands for hydrogen or alkyl with 1-4 carbon atoms and R2 means alkyl with 1-4 carbon atoms,

og deres syreaddisjonssalter,and their acid addition salts,

karakterisert vedatcharacterized by

a) for fremstilling av forbindelser med formel Iaa) for the preparation of compounds of formula Ia

hvori R_ har den ovennevnte betydning og R, betyr alkyl med 1-4 karbonatomer, avspaltes vann fra forbindelser med formel. hvori R^og R2har den ovennevnte betydning, eller b) for fremstilling av forbindelser med formel Ib hvori R» har den ovennevnte betydning, avspaltes resten R3fra forbindelser med formel III in which R_ has the above-mentioned meaning and R means alkyl with 1-4 carbon atoms, water is split off from compounds of formula in which R1 and R2 have the above meaning, or b) for the preparation of compounds of formula Ib in which R» has the above meaning, the residue R3 is cleaved from compounds of formula III

hvori R2har den ovennevnte betydning og R^ betyr en avspalt--bar rest, wherein R 2 has the above meaning and R 2 means a cleavable residue,

og de erholdte forbindelser med formel I overfores eventuelt i sine syreaddisjonssalter. and the obtained compounds of formula I are optionally transferred into their acid addition salts.

NO762085A 1975-06-24 1976-06-16 NO762085L (en)

Applications Claiming Priority (2)

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CH817475A CH613204A5 (en) 1975-06-24 1975-06-24 Process for the preparation of novel benzocycloheptathiophene derivatives
CH817375A CH615927A5 (en) 1975-06-24 1975-06-24 Process for the preparation of novel benzocycloheptathiophene derivatives

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JPS597963B2 (en) * 1977-06-28 1984-02-22 沖電気工業株式会社 Circular interpolation circuit in numerical control
DE3170504D1 (en) * 1980-09-02 1985-06-20 Sandoz Ag Piperidylidene derivatives, their production and pharmaceutical compositions containing them
JPS63205706A (en) * 1987-02-23 1988-08-25 Yaskawa Electric Mfg Co Ltd Arc machining control method
KR20010005791A (en) * 1997-04-03 2001-01-15 아베르그, 에이. 케이 Benzocycloheptathiophene compounds
JP5096500B2 (en) 2008-01-30 2012-12-12 日本臓器製薬株式会社 Piperidine derivatives
JP5083989B2 (en) * 2008-11-20 2012-11-28 日本臓器製薬株式会社 Medicaments containing piperidine derivatives
CN113227037A (en) * 2018-09-30 2021-08-06 北京生命科学研究所 Monohalogen or methyl substituted 5-HT2B antagonists with increased activity

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NL7606700A (en) 1976-12-28
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IE43917B1 (en) 1981-07-01
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IL49862A (en) 1980-11-30
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FR2316949B1 (en) 1979-10-12

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