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NO793473L - PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PHENYLALKYLAMINES - Google Patents

PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PHENYLALKYLAMINES

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Publication number
NO793473L
NO793473L NO793473A NO793473A NO793473L NO 793473 L NO793473 L NO 793473L NO 793473 A NO793473 A NO 793473A NO 793473 A NO793473 A NO 793473A NO 793473 L NO793473 L NO 793473L
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NO
Norway
Prior art keywords
acid
compounds
formula
acid addition
procedure
Prior art date
Application number
NO793473A
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Norwegian (no)
Inventor
Bernard Leon Zenitz
Original Assignee
Sterling Drug Inc
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
Priority claimed from US05/641,511 external-priority patent/US4069256A/en
Publication of NO793473L publication Critical patent/NO793473L/en
Application filed by Sterling Drug Inc filed Critical Sterling Drug Inc

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av fenyl-lavere-alkylaminer som kan brukes som anti-inflammatoriske midler. The present invention relates to a method for the production of phenyl-lower alkylamines which can be used as anti-inflammatory agents.

Mange typer organiske forbindelser kan brukes som anti-inflammatoriske midler, men mange slike midler er sure, Many types of organic compounds can be used as anti-inflammatory agents, but many such agents are acidic,

dette gjelder f.eks. a-(3-benzoylfenyl)propionsyre, vanligvis kjent som ketoprofen (britisk patent nr. 1.164.585). Slike sure midler er ofte irriterende, og de kan i visse tilfeller fremkalle mavesår når de tilføres oralt. Det er således et stort behov for anti-inflammatoriske midler som ikke er irriterende på mavens slimhinner, f.eks. forbindelser med en basisk aminfunksjon. Skjønt det i den kjemiske litteratur er beskrevet en rekke amin-substituerte forbindelser med anti-inflammatorisk aktivitet [se f.eks. US-patentene 3.770.748 og 3.803.127, (N-fenylpolymetyleniminer), US-patentene 3.772.311 og 3.773.772, (polymetylenimino-lavere-alkanoylpyrazoler), US-patent 3.773.944, (1-[3-aminopropyl]ftalaner), US-patent 3.801.594, (3-amino-lavere-alkylindoler), US-patent 3.810.985, (4-anilino-l,3,5-triaziner) og fransk patent 1.549.342, (4-[benzoylfenylmetyl]-morfoliner)], så er det ingen slike basiske forbindelser kommersielt tilgjengelige, og ingen er kjent for å være under- this applies e.g. α-(3-benzoylphenyl)propionic acid, commonly known as ketoprofen (British Patent No. 1,164,585). Such acidic agents are often irritating, and they can in certain cases induce stomach ulcers when administered orally. There is thus a great need for anti-inflammatory agents which are not irritating to the mucous membranes of the stomach, e.g. compounds with a basic amine function. Although a number of amine-substituted compounds with anti-inflammatory activity are described in the chemical literature [see e.g. US Patents 3,770,748 and 3,803,127, (N-phenylpolymethyleneimines), US Patents 3,772,311 and 3,773,772, (polymethyleneimino-lower-alkanoylpyrazoles), US Patent 3,773,944, (1-[3-aminopropyl ]phthalates), US Patent 3,801,594, (3-amino-lower-alkylindoles), US Patent 3,810,985, (4-anilino-1,3,5-triazines) and French Patent 1,549,342, (4 -[benzoylphenylmethyl]-morpholines)], then no such basic compounds are commercially available and none are known to be sub-

søkt av farmakologer for mulig kommersiell utvikling. Man har derfor stadig vært på jakt etter et effektivt ikke-surt, anti-inf lammatorisk middel som kan utvikles kommersielt. sought by pharmacologists for possible commercial development. There has therefore been a constant search for an effective non-acidic, anti-inflammatory agent that can be developed commercially.

Foreliggende oppfinnelse angår forbindelser méd formel: The present invention relates to compounds with the formula:

hvor gruppen representerer representerer lavere-alkyl eller hvor gruppen where the group represents represents lower alkyl or where the group

representerer hydrogen. represents hydrogen.

Med begrepene lavere alkyl forstås mettede, enverdige, allfatiske radikaler, slik som forgrenede radikaler med fra 1-4 karbonatomer, f.eks. metyl, etyl, propyl, isopropyl, butyl, sek-butyl og isobutyl. By the terms lower alkyl are meant saturated, monovalent, allphatic radicals, such as branched radicals with from 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and isobutyl.

Forbindelser med formel Ia hvor/C=X representerer Compounds of formula Ia where /C=X represents

fremstilles ved å omsette ét 3-(fenyl-CO)-fenyl-CHR_-halogenid med formel XIII med morfolin, ifølge reaksjonsskjemaet: hvor R~har samme betydning som angitt ovenfor og Hal er halogen. Reaksjonen utføres ved å omsette en oppløsning av halogenider med et molart overskudd av morfolin ved romtemperatur i et.inert organisk oppløsningsmiddel, f.eks. metanol, etanol, isopropanol eller DMF, hvorav det sistnevnte oppløsningsmiddel er det fore-trukne. Forbindelser med formel Ia hvor gruppen representerer fremstilles fra de tilsvarende forbindelser hvor is prepared by reacting one 3-(phenyl-CO)-phenyl-CHR_-halide of formula XIII with morpholine, according to the reaction scheme: where R~ has the same meaning as stated above and Hal is halogen. The reaction is carried out by reacting a solution of halides with a molar excess of morpholine at room temperature in an inert organic solvent, e.g. methanol, ethanol, isopropanol or DMF, of which the latter solvent is the preferred one. Compounds of formula Ia where the group represents are prepared from the corresponding compounds where

representerer C=0 ved å omdanne sistnevnte til oksimet represents C=0 by converting the latter to the oxime

(ved oppvarming av sistnevnte med hydroksylamin i et inert organisk oppløsningsmiddel, f.eks. en lavere alkanol) og redusere oksimet til aminet med natrium i en lavere alkanol. (by heating the latter with hydroxylamine in an inert organic solvent, e.g. a lower alkanol) and reducing the oxime to the amine with sodium in a lower alkanol.

De nye forbindelser fremstilt ifølge foreliggende oppfinnelse er forbindelsene med formel Ia, samt deres syreaddisjonssalter. Forbindelser med formel Ia i fri baseform kan om- The new compounds produced according to the present invention are the compounds of formula Ia, as well as their acid addition salts. Compounds of formula Ia in free base form can be re-

dannés til syreaddisjonssaltformen ved å reagere basen med en is formed into the acid addition salt form by reacting the base with a

j syre. På lignende måte kan den frie base regenereres fra syre-addis jonssaltet på vanlig måte, dvs. at man behandler saltene med en kald, svak vandig base, f.eks. alkalimetallkarbonater og alkalimetallbikarbonater. De således regenererte baser kan igjen omsettes med samme eller forskjellig syre hvoretter man får et annet syreaddisjonssalt. Alle de nye baser og alle deres syreaddisjonssalter er således lett omdannbare til hverandre. j acid. In a similar way, the free base can be regenerated from the acid addition salt in the usual way, i.e. by treating the salts with a cold, weak aqueous base, e.g. alkali metal carbonates and alkali metal bicarbonates. The thus regenerated bases can again be reacted with the same or different acid, after which a different acid addition salt is obtained. All the new bases and all their acid addition salts are thus easily convertible into each other.

Formel Ia omfatter således ikke bare selve basene med nevnte formel, men også representerer alle forbindelser med nevnte formel enten det er i form av en fri base eller i form Formula Ia thus not only includes the bases themselves with said formula, but also represents all compounds with said formula whether it is in the form of a free base or in the form

av et syreaddisjonssalt. Man har funnet at både basene og deres syreaddisjonssalter har de farmakologiske aktiviteter som er mer detaljert beskrevet nedenfor. Denne aktivitet kan utnyttes for farmasøytiske formål enten ved at man anvender de frie baser som sådan eller'deres syreaddisjonssalter, dvs. ved hjelp av syrer hvis anioner er uskadelige for dyreorganismer i effektive doser slik at man oppnår deønskede effekter uten at nevnte anioner frembringer bivirkninger. of an acid addition salt. Both the bases and their acid addition salts have been found to have the pharmacological activities described in more detail below. This activity can be exploited for pharmaceutical purposes either by using the free bases as such or their acid addition salts, i.e. by means of acids whose anions are harmless to animal organisms in effective doses so that the desired effects are achieved without said anions producing side effects.

Når man ønsker å utnytte de farmakologiske aktiviteter til de fremstilte forbindelser, er det foretrukket å bruke farmasøytisk akseptable salter. Skjønt vann-uoppløselighet, høy toksisitet og mangel av krystallinsk karakter kan gjøre noen spesielle salttyper uegnede eller mindre ønskelige for bruk i et gitt farmasøytisk tilfelle, så kan vann-uoppløselig eller toksiske salter omdannes til de tilsvarende farmasøytisk akseptable baser ved å dekomponere saltet med en vandig base slik det er forklart ovenfor, eller alternativt kan det omdannes til farmasøytisk akseptable syreaddisjonssalter ved en dobbelt de-komponeringsreaksjon som innbefatter anionet, f.eks. ved ioneut-bytting. When one wishes to utilize the pharmacological activities of the compounds produced, it is preferred to use pharmaceutically acceptable salts. Although water insolubility, high toxicity and lack of crystalline character may render some particular salt types unsuitable or less desirable for use in a given pharmaceutical case, water insoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable bases by decomposing the salt with a aqueous base as explained above, or alternatively it can be converted to pharmaceutically acceptable acid addition salts by a double decomposition reaction involving the anion, e.g. by ion exchange.

Foruten at de kan brukes for farmasøytiske formål, kan saltene brukes for å karakterisere eller identifisere derivater av de frie baser eller for å isolere eller å lense slike baser. Som alle andre syreaddisjonssalter kan slike rensningssalt-derivater hvis det er ønskelig, brukes for å regenererte de farmasøytisk akseptable frie baser ved at nevnte salter rea-geres med vandig base eller alternativt kan basen omdannes til farmasøytisk akseptable syreaddisjonssalter ved ioneutbytnings- Besides being used for pharmaceutical purposes, the salts can be used to characterize or identify derivatives of the free bases or to isolate or purify such bases. Like all other acid addition salts, such purification salt derivatives can, if desired, be used to regenerate the pharmaceutically acceptable free bases by reacting said salts with an aqueous base or alternatively the base can be converted into pharmaceutically acceptable acid addition salts by ion exchange

metoder. methods.

Det fremgår av det foregående at alle syreaddisjonssalter av de nye baser er brukbare og verdifulle forbindelser uansett hvorvidt de er oppløselige, toksiske, eller har en uegnet fysisk form for de rent farmasøytiske formål, og alle forbindelser inngår således i oppfinnelsen. It appears from the foregoing that all acid addition salts of the new bases are usable and valuable compounds regardless of whether they are soluble, toxic, or have an unsuitable physical form for purely pharmaceutical purposes, and all compounds are thus included in the invention.

Egenskapene til de fremstilte forbindelser ligger i basene eller de kationiske former av de nye N-{3-[R^-(fenyl)-C(=X)]-fenyl^lavere-alkyl}morfoliner og ikke i en spesiell syre-gruppe eller syreanion som er forbundet med saltformene av disse forbindelser, og disse syregrupper og anioner er i seg selv hverken nye eller kritiske og kan følgelig innbefatte ethvert syreanion eller syrelignende stoff som. er i stand til å danne salter med basene. I vandige oppløsninger vil således baseformen eller et vannoppløselig syreaddisjonssalt av forbindelser med formel I både ha en vandig protonert kation eller ammoniumion. The properties of the prepared compounds lie in the bases or the cationic forms of the new N-{3-[R^-(phenyl)-C(=X)]-phenyl^lower-alkyl}morpholines and not in a particular acid group or acid anion associated with the salt forms of these compounds, and these acid groups and anions are in themselves neither new nor critical and may therefore include any acid anion or acid-like substance which. are able to form salts with the bases. In aqueous solutions, the base form or a water-soluble acid addition salt of compounds of formula I will thus both have an aqueous protonated cation or ammonium ion.

Passende syreaddisjonssalter er således de som er fremstilt av forskjellige syrer, slik som maursyre, eddiksyre, isosmørsyre, alfa-merkaptopropionsyre, eplesyre, fumarsyre, rav-syre, succinaminsyre, vinsyre, sitronsyre, melkesyre, benzoe-syre, 4-metoksybenzosyre, ftalsyre, antranilinsyre, 1-naftalen-karboksylsyre, kanelsyre, cykloheksankarboksylsyre, mandelsyre, tropinsyre, krontonsyre, acetylendikarboksylsyre, sorbinsyre, 2-furankarboksylsyre, kolinsyre, pyrenkarboksylsyre, 2-pyridin-karboksylsyre, 3-indoleddiksyre, kininsyre, sulfaminsyre, metansulfonsyre, isetioninsyre, benzensulfonsyre, p-toluensulfon-syre, benzensulfinsyre, butylarsonsyre, dietylfosfonsyre, p-amino-fenylarsinsyre, fenylstibninsyre, fenylfosforsyre, metylfosfinsyre, fenylfosfinsyre, flussyre, saltsyre, hydrobromsyre, hydrojodsyre, perklorsyre, salpetersyre, svovelsyre, fosforsyre, blåsyre, fosforvolframsyre, molybdensyre, fosformolybdensyre, pyrofosfor-syre, arsensyre, pikrinsyr.e, pikroloninsyre, barbitursyre, bortri-fluorid og lignende. Suitable acid addition salts are thus those prepared from various acids, such as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1-naphthalene carboxylic acid, cinnamic acid, cyclohexane carboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, 2-furan carboxylic acid, cholic acid, pyrene carboxylic acid, 2-pyridine carboxylic acid, 3-indole acetic acid, quinic acid, sulfamic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphonic acid, p-amino-phenylarsinic acid, phenylstibnic acid, phenylphosphoric acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, prussic acid, phosphortungstic acid, molybdic acid, phosphormolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron tri-fluoride and the like.

Syreaddisjonssaltene kan fremstilles ved å omsette den frie base og syren i et organisk oppløsningsmiddel hvoretter man isolerer saltet direkte eller ved å konsentrere oppløsningen. The acid addition salts can be prepared by reacting the free base and the acid in an organic solvent, after which the salt is isolated directly or by concentrating the solution.

På grunn av tilstedeværelsen av et asymmetrisk senter, forbindelser med formel Ia, dvs. det karbonatom som er til-støtende til fenylringen til hvilket R^-gruppen er knyttet eller karbonatomer i ^CHN^-gruppen, så vil forbindelser med formel Ia eksistere i stereokjemiske isomere former som alle inngår i foreliggende oppfinnelse. Hvis det er ønskelig, kan man-isolere eller fremstille en spesiell stereokjemisk form, noe som kan gjøres ved at man bruker i seg selv kjente fremgangsmåter. Due to the presence of an asymmetric center, compounds of formula Ia, i.e. the carbon atom adjacent to the phenyl ring to which the R^ group is attached or carbon atoms in the ^CHN^ group, compounds of formula Ia will exist in stereochemical isomeric forms which are all included in the present invention. If desired, a particular stereochemical form can be isolated or produced, which can be done by using methods known per se.

I standard farmakologiske prøver har man funnet at forbindelser med formel Ia har meget verdifull anti-inflammatorisk aktivitet og kan følgelig brukes som anti-inflammatoriske midler. Den anti-inflammatoriske aktivitet ble bestemt ved å bruke In standard pharmacological tests, it has been found that compounds of formula Ia have very valuable anti-inflammatory activity and can therefore be used as anti-inflammatory agents. The anti-inflammatory activity was determined by using

(1) hemmingen av karrageenin-indusert fotødemprøve som i alt (1) the inhibition of carrageenin-induced foot edema test as in all

vesentlig er beskrevet av Van Arman et al., J. Pharmacol, Exptl. Therap. 150, 328 (1965) modifisert av Winter et al., Proe. Soc. Exp. Biol. og Med. 111, 544 (1962) og (2) en modifikasjon av hemmingen av hjelpemiddel-indusert arthritisprøven som er beskrevet av Pierson, J. Chronic Diseases 16, 863 (1963) og Glenn et al., Am. J. Vet. Res. 26, 1180 (1965), essentially described by Van Arman et al., J. Pharmacol, Exptl. Therapy. 150, 328 (1965) modified by Winter et al., Proe. Soc. Exp. Biol. and with. 111, 544 (1962) and (2) a modification of the inhibition of adjuvant-induced arthritis test described by Pierson, J. Chronic Diseases 16, 863 (1963) and Glenn et al., Am. J. Vet. Res. 26, 1180 (1965),

Forbindelser med formel. Ia kan fremstilles slik at de kan opparbeides i enhetsdoseformer for tabletter eller kapsler for oral tilførsel, enten alene eller i kombinasjon med egnet fortynningsmidler, slik som kalsiumkarbonat, stivelse, laktose, talkum, magnesiumstearat, gummi acacia og lignende. Videre kan forbindelsen opparbeides for oral tilførsel i vandig alkohol, glykol eller oljeoppløsninger eller i olje-vannemulsjoner på samme måte som man gjør i vanlig farmasøytisk industri. Compounds with formula. Ia can be prepared so that they can be processed into unit dosage forms for tablets or capsules for oral administration, either alone or in combination with suitable diluents, such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia and the like. Furthermore, the compound can be prepared for oral administration in aqueous alcohol, glycol or oil solutions or in oil-water emulsions in the same way as is done in the normal pharmaceutical industry.

Foreliggende forbindelsers molekylstruktur ble bestemt på basis av studier over spektra i infrarødt, ultrafiolett, samt kjernemagnetiske spektra, og bekreftet ved at det var en overens-stemmelse mellom beregnet og funnet verdi for de forskjellige elementer i forbindelsene. The molecular structure of the present compounds was determined on the basis of studies of spectra in infrared, ultraviolet and nuclear magnetic spectra, and confirmed by the fact that there was an agreement between calculated and found values for the various elements in the compounds.

Følgende eksempler illustrerer oppfinnelsen. Alle smeltepunkter er ukorrigerte. The following examples illustrate the invention. All melting points are uncorrected.

Eksempel 1 Example 1

En blanding av 28,62 g (0,09 mol) 4-(3-benzoylfenyl)metyl-morfolinhydroklorid og 9,6 3 g (0,14 mol) hydroksylaminhydroklorid i 35 ml 95% etanol og 27 ml vann, ble behandlet under omrøring med 21,68 g (0,54 mol) pulverformig natriumhydroksyd og blandingen ble tilbakeløpskokt i 1/2 time. Blandingen ble deretter avkjølt, A mixture of 28.62 g (0.09 mol) of 4-(3-benzoylphenyl)methylmorpholine hydrochloride and 9.6 3 g (0.14 mol) of hydroxylamine hydrochloride in 35 ml of 95% ethanol and 27 ml of water was treated under stirring with 21.68 g (0.54 mol) of powdered sodium hydroxide and the mixture was refluxed for 1/2 hour. The mixture was then cooled,

fortynnet med vann og ekstrahert flere ganger med benzen. Benzenekstraktene ga ved fordampning til tørrhet, et fast diluted with water and extracted several times with benzene. The benzene extracts, on evaporation to dryness, gave a solid

materiale som ble omkrystallisert fra benzen/heksan til 13,9 g 4-(3-benzoylfenyl)metylmorfolinoksim (smp. 145-167°C). material which was recrystallized from benzene/hexane to give 13.9 g of 4-(3-benzoylphenyl)methylmorpholinoxime (m.p. 145-167°C).

Eksempel 2 Example 2

En oppløsning av 8,12 g (0,027 mol) 4-(3-benzoylfenyl)-metyl-morfolinoksim i absolutt etanol, ble brakt til tilbakeløps-koking og behandlet med 6,45 g (0,28 mol) natriummetall tilsatt i små biter. Tilbakeløpskoking ble fortsatt inntil alt natrium var oppløst og oppløsningen ble deretter avkjølt, fortynnet med vann, surgjort med fortynnet saltsyre, inndampet til et volum på ca. 100 ml i vakuum og deretter ekstrahert med dietyleter. De organiske ekstrakter ble inndampet til tørrhet, en metanol-oppløsning av resten ble behandlet med eterholdig hydrogenklorid og oppløsningen inndampet til tørrhet, hvilket ga 8,3 g 4-{[3-(a-aminobenzyl)fenyl]metyl}morfolindihydrokloridmonohydrat, smp. 270-274°C. A solution of 8.12 g (0.027 mol) of 4-(3-benzoylphenyl)-methyl-morpholinoxime in absolute ethanol was brought to reflux and treated with 6.45 g (0.28 mol) of sodium metal added in small portions . Refluxing was continued until all the sodium had dissolved and the solution was then cooled, diluted with water, acidified with dilute hydrochloric acid, evaporated to a volume of approx. 100 ml in vacuo and then extracted with diethyl ether. The organic extracts were evaporated to dryness, a methanol solution of the residue was treated with ethereal hydrogen chloride and the solution evaporated to dryness, yielding 8.3 g of 4-{[3-(α-aminobenzyl)phenyl]methyl}morpholine dihydrochloride monohydrate, m.p. 270-274°C.

Eksempel 3 Example 3

En oppløsning av 11,0 g (0,126 mol) morfolin i 24 ml dimetylformamid ble omrørt ved hjelp av ytre avkjøling i et vann-bad og behandlet iløpet av 10 minutter med en oppløsning av 17,35 g (0,06 mol) 1-(3-bénzoylfenyl)-1-brometan i 24 ml dimetylformamid. Etter at tilsetningen var fullstendig, ble blandingen omrørt i ytterligere 1 time ved romtemperatur. Den ble deretter filtrert, filteret vasket med eter og filtratet helt over i 125 ml vann og blandingen ekstrahert to ganger med eter. Isolering av produktet i form av en fri base fra eterekstraktene på vanlig måte gå 14,8 g av et oljeaktig produkt som ble kromato-grafert på aluminiumoksyd idet man som elueringsmiddel brukte en 1:1 eter/heksanoppløsning, og dette ga 12 g av 4-[l-(3-benzoylfenyl)etyl]morfolin som en blekt gul olje. A solution of 11.0 g (0.126 mol) morpholine in 24 ml dimethylformamide was stirred with the aid of external cooling in a water bath and treated during 10 minutes with a solution of 17.35 g (0.06 mol) 1- (3-benzoylphenyl)-1-bromoethane in 24 ml of dimethylformamide. After the addition was complete, the mixture was stirred for an additional 1 hour at room temperature. It was then filtered, the filter washed with ether and the filtrate poured into 125 ml of water and the mixture extracted twice with ether. Isolation of the product in the form of a free base from the ether extracts in the usual way yielded 14.8 g of an oily product which was chromatographed on alumina using a 1:1 ether/hexane solution as eluent, and this gave 12 g of 4 -[l-(3-benzoylphenyl)ethyl]morpholine as a pale yellow oil.

Analyse: Analysis:

Beregnet for C19<H>21N02: C 77,26; H 7,17; N 4,74 Calculated for C19<H>21N02: C 77.26; H 7.17; N 4.74

Funnet: C 76,95; H 7,11; N 4,61. Found: C 76.95; H 7.11; N 4.61.

Biologiske prøveresultater Biological test results

Nevnte N-{3-[F^-(fenyl)-C(=X)]-fenyl-lavere-alkyl}-morfoliner med formel Ia er blitt prøvet i de kjente karragenin-ødem (CE) og hjelpemiddel arthritis (AA) prøver, og man fant at de hadde anti-inflammatorisk aktivitet. De oppnådde resul-tater angitt som prosenthemming.ved en dose uttrykt i millimol (yM)/kg kroppsvekt, er angitt i tabell A nedenfor. For sammen- lignende formål har man også oppgitt data som ble oppnådd i en karrageeninødemprøve med en referanseforbindelse (angitt "Ref."), dvs. 4-[(3-benzoylfenyl)metyl]morfolin, beskrevet i fransk patent 1.549.342. Alle data ble oppnådd ved oral tilførsel. Said N-{3-[F^-(phenyl)-C(=X)]-phenyl-lower-alkyl}-morpholines of formula Ia have been tried in the known carrageenan edema (CE) and aid arthritis (AA) samples, and they were found to have anti-inflammatory activity. The results obtained, expressed as percentage inhibition at a dose expressed in millimoles (µM)/kg body weight, are set out in Table A below. For comparative purposes, data obtained in a carrageenan edema sample with a reference compound (designated "Ref."), i.e. 4-[(3-benzoylphenyl)methyl]morpholine, described in French patent 1,549,342, have also been provided. All data were obtained by oral administration.

Claims (1)

Fremgangsmåte for fremstilling av terapeutisk virksomme forbindelser med formelen:Procedure for the preparation of therapeutically active compounds of the formula: hvor gruppen where the group representerer represents og R, representerer lavere alkyl, eller hvor gruppen and R, represents lower alkyl, or where the group representerer represents og R3representerer hydrogen, samt farmasøytisk akseptable syreaddisjonssalter derav,karakterisert vedat man: a) fremstiller en forbindelse and R3 represents hydrogen, as well as pharmaceutically acceptable acid addition salts thereof, characterized in that: a) a compound is prepared representerer represents og R, representerer lavere alkyl, ved å omsette en forbindelse med formelen: med morfolin, eller b) fremstiller en forbindelse and R, represents lower alkyl, by reacting a compound of the formula: with morpholine, or b) prepares a compound representerer represents og R-. er hydrogen, ved å redusere med natrium i en lavere alkanol en forbindelse med formel Ia hvor X er og R-. er hydrogen, og, om ønsket, omdanner et således fremstilt syreaddisjonssalt til et annet syreaddisjonssalt.and R-. is hydrogen, by reducing with sodium in a lower alkanol a compound of formula Ia where X is and R-. is hydrogen, and, if desired, converts an acid addition salt thus prepared into another acid addition salt.
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US4339576A (en) 1980-11-19 1982-07-13 Sterling Drug Inc. Anti-asthmatic, anti-allergic, anti-cholinergic, bronchodilator and anti-inflammatory 1-[(benzoylphenyl)-lower-alkyl]piperidines and analogs thereof
US4396765A (en) 1981-08-24 1983-08-02 Sterling Drug Inc. Amino-1-[(halophenyl)-lower-alkyl]piperidines
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