DK150509B - ANALOGY PROCEDURE FOR PREPARING CIS-4- (3-PHENYL-2-METHYL-PROPYL) -2,6-DIMETHYL MORPHOLINES - Google Patents
ANALOGY PROCEDURE FOR PREPARING CIS-4- (3-PHENYL-2-METHYL-PROPYL) -2,6-DIMETHYL MORPHOLINES Download PDFInfo
- Publication number
- DK150509B DK150509B DK355180AA DK355180A DK150509B DK 150509 B DK150509 B DK 150509B DK 355180A A DK355180A A DK 355180AA DK 355180 A DK355180 A DK 355180A DK 150509 B DK150509 B DK 150509B
- Authority
- DK
- Denmark
- Prior art keywords
- phenyl
- cis
- compound
- formula
- general formula
- Prior art date
Links
Classifications
-
- 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
- C07D295/02—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
150509150509
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte, racemiske eller optisk aktive cis-4-(3-phen-yl-2-methylpropyl)-2,6-dimethylmorpholiner med den almene formel IThe present invention relates to an analogous process for the preparation of novel, racemic or optically active cis-4- (3-phenyl-2-methylpropyl) -2,6-dimethylmorpholines of the general formula I
\h3 5 hvor R betegner ethyl eller phenyl, eller fysiologisk tolerable syreadditionssalte eller N-oxider af disse forbindelser, hvilken fremgangsmåde er ejendommelig ved, at manwherein R represents ethyl or phenyl, or physiologically tolerable acid addition salts or N-oxides of these compounds, which process is characterized in that
a) omsætter et halogenid med den almene formel II(a) reacting a halide of the general formula II
R.XH3R.XH3
|j CH3 II| j CH3 II
10 hvor R har den ovenfor anførte betydning, og Y betegner chlor, brom eller iod, med en forbindelse med formlen IIIWherein R is as defined above and Y is chlorine, bromine or iodine, with a compound of formula III
£H3 r\ HNw 150509 2 eller£ H3 r \ HNw 150509 2 or
b) reducerer en forbindelse med den almene formel IVb) reducing a compound of general formula IV
^\/Ch3 £h3 H3C>r^ Γ3 Γ\ \h2 hvor R har den ovenfor anførte betydning, og den ene af de to 5 stiplede linjer betegner en yderligere binding, ellerWhere R has the meaning given above, and one of the two 5 dotted lines represents an additional bond, or
c) omsætter en forbindelse med formlen Vc) reacting a compound of formula V
£H3 r^il Γ3 O h <£ H3 r ^ il Γ3 O h <
med en forbindelse, som afgiver en carboniumion med den almene formel VIwith a compound which gives off a carbonium ion of the general formula VI
Q *Q *
10 ~ VI10 ~ VI
hvor R har den ovenfor anførte betydning, eller 3 150509 d) omsætter en forbindelse med den almene formel Vil R\XH3where R has the meaning given above, or 3) translates a compound of the general formula Will R \ XH3
H3C/>^NH3C /> ^ N
d J Vild J Will
^CHO^ CHO
hvor R har den ovenfor anførte betydning, under hydrogenerende betingelser med en forbindelse med formlen III, eller at man til frem-5 stilling af et N-oxid behandler en forbindelse med formlen I med hydrogenperoxid eller persyrer, eller at man til fremstilling af et fysiologisk tolerabelt syreadditionssalt på i og for sig kendt måde omsætter en base med formlen I med den nødvendige syre, hvorefter man, om ønsket, opspalter et vundet racemat i de optiske antipoder.wherein R has the meaning given above, under hydrogenating conditions with a compound of formula III, or to prepare a compound of formula I with hydrogen peroxide or peracids, or to prepare a physiological tolerable acid addition salt in a manner known per se, reacting a base of formula I with the necessary acid and then, if desired, splitting a won racemate into the optical antipodes.
10 Ved fremgangsmådevariant a) omsættes et halogenid med formlen II med en amin med formlen III, hensigtsmæssigt i et inert opløsningsmiddel, f.eks. i en ether såsom diethylether, tetrahydrofuran eller dioxan eller i dimethylsulfoxid, fortrinsvis i en højerekogende alkohol, f.eks. ethylenglycol eller glycerol, i nærværelse af en base, f.eks.In process variant a), a halide of formula II is reacted with an amine of formula III, conveniently in an inert solvent, e.g. in an ether such as diethyl ether, tetrahydrofuran or dioxane or in dimethyl sulfoxide, preferably in a higher boiling alcohol, e.g. ethylene glycol or glycerol, in the presence of a base, e.g.
15 triethylamin eller et overskud af aminen med formlen III. Blandingen omsættes fortrinsvis i et temperaturområde mellem 50 og 150°C. Særlig foretrukket er som opløsningsmiddel ethylenglycol og en temperatur på 100 - 110°C.15 triethylamine or an excess of the amine of formula III. The mixture is preferably reacted in a temperature range between 50 and 150 ° C. Particularly preferred as solvent is ethylene glycol and a temperature of 100 - 110 ° C.
Ifølge fremgangsmådevariant b) reduceres en forbindelse med formlen 20 IV. Når der som udgangsmateriale med formlen IV anvendes en forbindelse, hvor dobbeltbindingen sidder i α-stilling i forhold til mor-pholingruppen, kan reduktionen foretages katalytisk eller med myresyre.According to process variant b), a compound of formula 20 IV is reduced. When a compound of formula IV is used as a compound in which the double bond sits in the α position relative to the morpholine group, the reduction can be carried out catalytically or with formic acid.
Som katalysatorer kan især anvendes ædelmetalkatalysatorer, f.eks.Particularly suitable as catalysts are precious metal catalysts, e.g.
25 platin, palladium, der eventuelt er udfældet på kul, samt Raney-nik-kel. Der foretrækkes palladium på kul. Opløsningsmidler, der er egnede til den katalytiske reduktion, er carbonhydrider såsom benzen.25 platinum, optionally precipitated on coal, and Raney-nickel. Palladium on coal is preferred. Solvents suitable for the catalytic reduction are hydrocarbons such as benzene.
150509 4 toluen eller xylen samt alkoholer såsom methanol eller ethanol. Der foretrækkes toluen. Som reaktionstemperatur vælges fortrinsvis et interval mellem 0 og 50°C, fortrinsvis stuetemperatur. Reduktionen af enaminen med myresyre udføres fortrinsvis i fravær af et opløsnings-5 middel, og til enaminen dryppes myresyren ved en temperatur på 0 -100°C, fortrinsvis 50 - 70°C, om nødvendigt under afkøling.Toluene or xylene and alcohols such as methanol or ethanol. Toluene is preferred. As the reaction temperature, a range between 0 and 50 ° C, preferably room temperature, is preferably selected. The reduction of the enamine with formic acid is preferably carried out in the absence of a solvent, and to the enamine the formic acid is dropped at a temperature of 0-100 ° C, preferably 50 - 70 ° C, if necessary under cooling.
Ved anvendelse af et udgangsmateriale med formlen IV, hvor dobbeltbindingen sidder i o-stilling i forhold til phenylgruppen, kan reduktionen foretages katalytisk. Som katalysator kan der her for-10 trinsvis anvendes platin eller palladium, og som opløsningsmiddel anvendes vand eller alkohol. For at undgå en mulig hydrolyse, sættes der til reaktionsblandingen mindst ét ækvivalent syre, fortrinsvis saltsyre.By using a starting material of formula IV wherein the double bond is in the o-position relative to the phenyl group, the reduction can be catalytically carried out. Here, preferably, platinum or palladium can be used as catalyst, and water or alcohol is used as a solvent. To avoid possible hydrolysis, at least one equivalent acid, preferably hydrochloric acid, is added to the reaction mixture.
Alkyleringen af forbindelsen med den almene formel V ifølge frem-15 gangsmådevariant c) foretages i nærværelse af en egnet mængde af en Friedel-Crafts-katalysator. Som katalysatorer kan anvendes de kendte Friedel-Crafts-katalysatorer, f.eks. aluminiumchlorid, jernchlorid, zinkchlorid, bortrifluorid, tinchlorid, hydrogenfluorid, svovlsyre og phosphorsyre. Til den foreliggende opfindelses formål foretrækkes 20 især svovlsyre.The alkylation of the compound of general formula V according to process variant c) is carried out in the presence of a suitable amount of a Friedel-Crafts catalyst. As known catalysts can be used the known Friedel-Crafts catalysts, e.g. aluminum chloride, iron chloride, zinc chloride, boron trifluoride, tin chloride, hydrogen fluoride, sulfuric acid and phosphoric acid. For the purposes of the present invention, sulfuric acid is particularly preferred.
Anvendelsen af et inert organisk opløsningsmiddel er ikke tvingende nødvendig ved denne fremgangsmådevariant, men den foretrækkes.The use of an inert organic solvent is not imperative in this process variant, but it is preferred.
Som inert organisk opløsningsmiddel kan især anvendes alkaner såsom hexan eller cyclohexan, chlorerede carbonhydrider såsom chloroform, 25 ethylendichlorid eller methylenchlorid, hvorhos der især foretrækkes methylenchlorid. Alkyleringsreaktionstemperaturen er ikke kritisk, men ligger i reglen mellem 0 og 50°C, fortrinsvis mellem 18 og 20°C.As an inert organic solvent, alkanes such as hexane or cyclohexane, chlorinated hydrocarbons such as chloroform, ethylene dichloride or methylene chloride, in which methylene chloride is particularly preferred, may be used. The alkylation reaction temperature is not critical, but is generally between 0 and 50 ° C, preferably between 18 and 20 ° C.
Fortrinsvis og især i de tilfælde, hvor der anvendes svovlsyre, ekstraheres det vundne produkt efter endt reaktion i saltform med et 30 inert organisk opløsningsmiddel, f.eks. methylenchlorid. Om ønsket kan den frie amin fås ved anvendelse af en egnet base, f.eks. natriumhydroxidopløsning, kaliumhydroxidopløsning, sodaopløsning, potaske eller calciumhydroxid.Preferably, and especially in the cases where sulfuric acid is used, the resulting product is extracted in salt form after reaction with an inert organic solvent, e.g. methylene chloride. If desired, the free amine can be obtained using a suitable base, e.g. sodium hydroxide solution, potassium hydroxide solution, soda solution, potash or calcium hydroxide.
5 1505095 150509
Foretrukne forbindelser, som afgiver carboniumionen med den almene formel VI, er de tilsvarende tertiære alkoholer, f.eks. 2-methyl-2-bu-tanol eller tert.chlorider såsom 2-chlor-2-methylbutan.Preferred compounds which give off the carbonium ion of general formula VI are the corresponding tertiary alcohols, e.g. 2-methyl-2-butanol or tert-chlorides such as 2-chloro-2-methylbutane.
Omsætningen mellem det substituerede kanelaldehyd med formlen VII 5 og cis-2,6-dimethylmorpholinen med formlen III foretages under hydrogenerende betingelser, f.eks. under anvendelse af en palladiumkatalysator, f.eks. i mehanol.The reaction between the substituted cinnamaldehyde of formula VII 5 and the cis-2,6-dimethylmorpholine of formula III is carried out under hydrogenating conditions, e.g. using a palladium catalyst, e.g. in mehanol.
Til fremstilling af N-oxiderne med forbindelserne med formlen I behandles en forbindelse med formlen I med hydrogenperoxid eller en 10 persyre. Som opløsningsmidler kan der i de tilfælde, hvor der anvendes hydrogenperoxid som oxidationsmiddel, anvendes alkoholer såsom methanol, ethanol eller isopropanol, fortrinvis isopropanol. Foretrukne reaktionstemperaturer ligger mellem 0 og 50°C, særlig foretrukket ved 40°C. Som persyrer kan der f.eks. anvendes pereddikesyre, perben-15 zoesyre, methachlorperbenzoesyre eller peradipinsyre. Som opløsningsmiddel for persyrerne kan der fortrinsvis anvendes halogenerede carbonhydrider såsom methylenchlorid, chloroform eller ethylenchlorid.To prepare the N-oxides with the compounds of formula I, a compound of formula I is treated with hydrogen peroxide or a peracid. As solvents, in cases where hydrogen peroxide is used as the oxidizing agent, alcohols such as methanol, ethanol or isopropanol may be used, preferably isopropanol. Preferred reaction temperatures are between 0 and 50 ° C, especially preferably at 40 ° C. As peracids, e.g. peracetic acid, perbenzoic acid, methachloroperbenzoic acid or peradipic acid are used. As the solvent for the peracids, halogenated hydrocarbons such as methylene chloride, chloroform or ethylene chloride may preferably be used.
Egnede reaktionstemperaturer er som ovenfor beskrevet i forbindelse med omsætningen med hydrogenperoxid.Suitable reaction temperatures are as described above in connection with the reaction with hydrogen peroxide.
20 Forbindelser med formlen I danner salte med fysiologisk tolerable organiske og uorganiske syrer. Til denne gruppe hører fortrinsvis hydrogenhalogenidsyrerne, f.eks. saltsyre og brombrintesyre, samt phosphorsyre, salpetersyre og mono- og bifunktionelle carboxylsyrer og hydroxycarboxylsyrer, f.eks. eddikesyre, maleinsyre, ravsyre, 25 fumarsyre, vinsyre, citronsyre, salicylsyre, sorbinsyre og mælkesyre, og endelig sulfonsyrer, f.eks. 1,5-naphthalen-disulfonsyre. Fremstillingen af sådanne salte foregår på i og for sig kendt måde.Compounds of formula I form salts with physiologically tolerable organic and inorganic acids. This group preferably belongs to the hydrogen halide acids, e.g. hydrochloric and hydrochloric, as well as phosphoric, nitric and mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid, and finally sulfonic acids, e.g. 1,5-naphthalene-disulfonic acid. The preparation of such salts takes place in a manner known per se.
Udgangsmaterialerne med formlerne II og VI er kendte forbindelser. Udgangsmaterialerne III og IV er kendte som cis/trans-blandinger.The starting materials of formulas II and VI are known compounds. The starting materials III and IV are known as cis / trans mixtures.
30 Cis-udgangsmaterialerne III og IV kan fremstilles analogt med fremgangsmåden til fremstilling af cis/trans-blandingerne.The cis starting materials III and IV can be prepared analogously to the process for preparing the cis / trans mixtures.
6 1505096 150509
De udgangsmaterialer med formlen IV, hvor dobbeltbindingen sidder i α-stilling i forhold til morpholingruppen, kan f.eks. fremstilles ved omsætning af et på tilsvarende måde substitueret phenyl-2-methyl-propionaldehyd med cis-2,6-dimethylmorpholin. Hydrogeringen af de 5 således vundne forbindelser med formlen IV foretages hensigtsmæssigt in situ.The starting materials of formula IV, in which the double bond sits in the α position relative to the morpholine group, can be e.g. is prepared by reacting a similarly substituted phenyl-2-methyl-propionaldehyde with cis-2,6-dimethylmorpholine. The hydrogenation of the 5 compounds thus obtained of formula IV is conveniently carried out in situ.
De udgangsmaterialer med formlen IV, hvor dobbeltbindingen sidder i α-stilling i forhold til phenylgruppen, kan f.eks. fremstilles ved omsætning af et halogenid, som svarer til formlen II, men som dog i 10 α-stilling i forhold til phenylgruppen har en dobbeltbinding, med cis-2,6-dimethylmorpholin.The starting materials of formula IV wherein the double bond is in the α-position relative to the phenyl group can be e.g. is prepared by reacting a halide similar to Formula II, but which, however, in a 10 α position relative to the phenyl group has a double bond, with cis-2,6-dimethylmorpholine.
Forbindelsen med formlen V kan fremstilles ved, at forbindelsen med formlen VIIIThe compound of formula V can be prepared by the compound of formula VIII
|1 CH3 V'" 15 blandes med forbindelsen med formlen III og hydrogeneres katalytisk.The mixture is mixed with the compound of formula III and catalytically hydrogenated.
Som opløsningsmiddel anvendes fortrinsvis et organisk opløsningsmiddel, f.eks. en alkohol såsom methanol. Temperaturen er ikke kritisk, men ligger i reglen mellem 0 og 50°C.Preferably, as an solvent, an organic solvent is used, e.g. an alcohol such as methanol. The temperature is not critical, but is usually between 0 and 50 ° C.
Ved den katalytiske hydrogenering anvendes de sædvanlige hydro-20 generingskatalysatorer, f.eks. platin, Raney-nikkel eller palladium, fortrinsvis 5%'s palladium/kul.In the catalytic hydrogenation, the usual hydrogenation catalysts, e.g. platinum, Raney nickel or palladium, preferably 5% palladium / carbon.
De omhandlede forbindelser indeholder i den propylenkæde, som forbinder morpholingruppen med den p-substituerede phenylgruppe, et asymmetrisk carbonatom og kan derfor optræde i form af race-25 materne og i form af de optiske antipoder. De optiske antipoder kan fås ud fra de fremstillede racemater ved opspaltning med optisk aktive 7 150509 syrer, f.eks. med (+)-camphersyre, (+)-campher-10-sulfonsyre, Ο,Ο'-dibenzoylvinsyre (L- eller D-form), L(+)-vinsyre, D(-)-vinsyre, L(+)-glutaminsyre-4-sulfonat, L(-)-æblesyre eller D(+) -æblesyre.The compounds of this invention contain, in the propylene chain connecting the morpholine group to the β-substituted phenyl group, an asymmetric carbon atom and can therefore appear in the form of the racemates and in the form of the optical antipodes. The optical antipodes can be obtained from the prepared racemates by digestion with optically active acids, e.g. with (+) - camphoric acid, (+) - campher-10-sulfonic acid, Ο, Ο'-dibenzoyltartaric acid (L or D form), L (+) - tartaric acid, D (-) - tartaric acid, L (+) -glutamic acid 4-sulfonate, L (-) - malic or D (+) malic.
Denne opspaltning kan foretages ved sædvanlige spaltningsmetoder.This cleavage can be carried out by conventional cleavage methods.
5 De omhandlede aktivstoffer er på grund af deres fungistatiske og fungicide virkning velegnede til bekæmpelse af infektioner, der fremkaldes af svampe og gærarter, f.eks. af slægterne Candida, Tricho-phyter eller Histoplasma. De er især virksomme mod Candida-arter såsom Candida albicans og er fortrinsvis velegnede til lokal terapi af 10 overfladeinfektioner på huden og på slimhinderne, især i genitalkanalen, f.eks. vaginitis, især forårsaget af Candida. Applikationsformen er fortrinsvis den lokale, så at aktivstofferne anvendes som terapeutisk virksomme præparater i form af salver, stikpiller, suppositorier eller ovula.Due to their fungistatic and fungicidal activity, the active substances in question are suitable for the control of infections caused by fungi and yeasts, e.g. of the genera Candida, Trichophytes or Histoplasm. They are particularly effective against Candida species such as Candida albicans and are preferably suitable for local therapy of 10 surface infections on the skin and on the mucous membranes, especially in the genital tract, e.g. vaginitis, especially caused by Candida. The form of application is preferably local, so that the active substances are used as therapeutically active preparations in the form of ointments, suppositories, suppositories or ovules.
15 Fremstillingen af de farmaceutiske præparater kan foretages på i og for sig kendt måde ved blanding af aktivstofferne med sædvanlige organiske eller uorganiske bærestoffer og/eller hjælpemidler, f.eks. vand, gelatine, lactose, stivelse, magnesiumstearat, talkum, vegetabilske olier, polyalkylenglycoler, vaseline, konserverings-, stabilise-20 rings-, befugtnings- eller emulgeringsmidler, salte til ændring af det osmotiske tryk eller pufferstoffer.The preparation of the pharmaceutical compositions may be carried out in a manner known per se by mixing the active substances with usual organic or inorganic carriers and / or adjuvants, e.g. water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, preservatives, stabilizers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffer.
Doseringen foretages efter individuelle behov, men en foretrukken dosering turde være en daglig applikation af 1 - 2 tabletter, som indeholder 50 - 100 mg aktivstof, i nogle dage. Salverne indeholder 25 hensigtsmæssigt 0,3 - 5%, fortrinsvis 0,5 - 2%, navnlig 0,5 - 1%, aktivstof. Den nedenfor anførte forsøgsrapport og de i tabellen viste resultater giver ligeledes fagmanden den nødvendige information til dosering af aktivstofferne.The dosage is done according to individual needs, but a preferred dosage should be a daily application of 1-2 tablets containing 50-100 mg of active substance for a few days. The ointments conveniently contain 0.3 - 5%, preferably 0.5 - 2%, especially 0.5 - 1%, active substance. The test report listed below and the results shown in the table also provide the skilled person with the necessary information for dosing the active substances.
De omhandlede forbindelser er afprøvet for virkning mod Candida 30 albicans ved den i Path. Microbiol. 23: 62 - 68 (1960) beskrevne vaginal-candidiasis-test på rotter, og der er opnået følgende resultater: \ 8 150509The compounds of this invention have been tested for efficacy against Candida 30 albicans at that in Path. Microbiol. 23: 62-68 (1960), vaginal candidiasis tests in rats and the following results have been obtained: \ 8 150509
Forbindelse Koncentration i %, ved hvilken der indtrådte en "ED^g"-virkning 5 cis-4-[3-(p-tert.amyl-phenyl)- 2-methylpropyl]-2,6-dimethyl-morpholin 0,01 cis-4-(3-[p-(a,a-dimethyl-10 benzyl)phenyl]-2-methylpro- pyl)-2,6-dimethylmorpholin 0,01 I svensk fremlæggelsesskrift nr. 437.022 er bl.a. beskrevet de to forbindelser 4-[3-(p-tert.amyl-phenyl)-2-methylpropyl] -2,6-dimethyl-15 morpholin og 4-[3-[p-(a,a-dimethyl-dibenzyl)phenyl]-2-methylprop-yl]-2,6-dimethylmorpho!in. De ifølge dette fremlæggelsesskrift fremstillede forbindelser er cis/trans-blandinger, medens de forbindelser, der er fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse, er cis-forbindelser.Compound Concentration in% at which an "ED ^g" effect occurred 5 cis-4- [3- (p-tert.amyl-phenyl) -2-methylpropyl] -2,6-dimethyl-morpholine 0.01 cis-4- (3- [p- (a, a-dimethyl-10-benzyl) phenyl] -2-methylpropyl) -2,6-dimethylmorpholine 0.01 In Swedish Patent Specification No. 437,022, described the two compounds 4- [3- (p-tert.amyl-phenyl) -2-methylpropyl] -2,6-dimethyl-morpholine and 4- [3- [p- (α, α-dimethyl-dibenzyl) phenyl] -2-methylprop-yl] -2,6-dimethylmorpho Clin. The compounds of this disclosure are cis / trans mixtures, while the compounds prepared by the process of the present invention are cis compounds.
20 De omhandlede cis-forbindelser, dvs. forbindelserne med formlen I og de fysiologisk tolerable syreadditionssalte og N-oxider deraf, har en antimycotisk virkning, som ganske uventet er væsentligt højere end den antimycotiske virkning, som de i svensk fremlæggelsesskrift nr.The cis compounds in question, viz. the compounds of formula I and the physiologically tolerable acid addition salts and N-oxides thereof have an antimycotic effect which, quite unexpectedly, is substantially higher than the antimycotic effect which they in Swedish disclosure no.
437.022 beskrevne cis/trans-blandinger har. Fx har det ved sammen-25 ligningsforsøg vist sig, at cis/trans-blandingerne mod Candida albicans i et vaginal-candidiasis-forsøg på rotter (Path. Microbiol. 23: 62-68 (1960) har EDgg ved en koncentration på 0,1%, medens cis-forbindelserne med formlen I, der fremstilles ved fremgangsmåden ifølge den foreliggende opfindelse, som ovenfor angivet har ED^g ved en 30 koncentration på 0,01%.437,022 cis / trans mixtures described have. For example, in comparison studies, it has been found that the cis / trans mixtures against Candida albicans in a vaginal candidiasis study in rats (Path. Microbiol. 23: 62-68 (1960) have EDgg at a concentration of 0 1 c, while the cis compounds of formula I prepared by the process of the present invention, as indicated above, have ED 2 g at a concentration of 0.01%.
9 1505099 150509
Opfindelsen belyses nærmere ved nedenstående eksempler:The invention is further illustrated by the following examples:
Eksempel 1.Example 1.
230 g 3-(p-tert.amyl-phenyl)-2-methylpropionaldehyd og 137 g cis- 2,6-dimethylmorpholin opvarmes til kogning under tilbagesvaling i 1000 5 ml toluen med vandfraskiller under nitrogenatmosfære i 16 timer, indtil vandfraspaltningen er afsluttet. Ved stuetemperatur tilsættes under nitrogenatmosfære 17,5 g 5%'s palladium/kul, og der hydrogeneres, indtil hydrogenoptagelsen er endt, katalysatoren frafiltreres, og toluenet afdampes i vakuum. Ved destillation af remanensen fås 10 rent cis-4-[3-(p-tert.amyl-phenyl)-2-methylpropyl]-2,6-dimethylmor-pholin, kogepunkt 120°C/0,1 mm Hg.230 g of 3- (p-tert.amyl-phenyl) -2-methylpropionaldehyde and 137 g of cis-2,6-dimethylmorpholine are heated to reflux in 1000 5 ml of toluene with water separator under nitrogen atmosphere for 16 hours until the water splitting is completed. At room temperature, 17.5 g of 5% palladium / carbon are added under nitrogen atmosphere and hydrogenated until hydrogen uptake is complete, the catalyst is filtered off and the toluene is evaporated in vacuo. Distillation of the residue gives 10 pure cis-4- [3- (p-tert.amyl-phenyl) -2-methylpropyl] -2,6-dimethylmorpholine, boiling point 120 ° C / 0.1 mm Hg.
Eksempel 2.Example 2.
På med eksempel 1 analog måde fås ved omsætning af 3-[p-(o,o-dime-thyi-benzyI)phenyl]-2-methylpropionaldehyd med cis-2,6-dimethyf-15 morpholin og hydrogenering cis-4-(3-[p-(a,a-dimethyl-benzyl)phe- nyl]-2-methylpropyl)-2,6-dimethylmorpholm, kogepunkt 162°C/0,04 mm Hg.In Example 1, analogously, by reaction of 3- [p- (o, o -dime-thi-benzyl) phenyl] -2-methylpropionaldehyde with cis-2,6-dimethyl-morpholine and hydrogenation cis-4- ( 3- [p- (α, α-Dimethyl-benzyl) phenyl] -2-methylpropyl) -2,6-dimethylmorpholm, boiling point 162 ° C / 0.04 mm Hg.
Eksempel 3.Example 3
Til 1223 g cis-4-(2-methyl-3-phenylpropyl)-2,6-dimethylmorpholin i 4 20 liter methylenchlorid dryppes i løbet af 45 minutter ved -5°C 4941 g koncentreret svovlsyre og derefter i løbet af 60 minutter 520 g 2-me-thyl-2-butanol. Under isafkøling sættes vand til reaktionsopløsningen, og den vandige fase ekstraheres flere gange med methylenchlorid. De organiske ekstrakter vaskes med natriumhydroxidopløsning og derefter 25 med vand, tørres og inddampes, og det olieagtige cis-4-[3-(p-tert.a-myl-phenyl)-2-methylpropyl]-2,6-dimethylmorpholin destilleres i vakuum, kogepunkt 120°C/0,1 mm Hg.To 1223 g of cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine in 4 20 liters of methylene chloride are dropped over 45 minutes at -5 ° C 4941 g of concentrated sulfuric acid and then within 60 minutes 520 g of 2-methyl-2-butanol. Under ice-cooling, water is added to the reaction solution and the aqueous phase is extracted several times with methylene chloride. The organic extracts are washed with sodium hydroxide solution and then with water, dried and evaporated and the oily cis-4- [3- (p-tert-a-methyl-phenyl) -2-methylpropyl] -2,6-dimethylmorpholine is distilled off vacuum, boiling point 120 ° C / 0.1 mm Hg.
10 15050910 150509
Det som udgangsmateriale anvendte cis-4-(2-methyl-3-phenylpropy|)- 2,6-dimethylmorpholin kan fremstilles på følgende måde:The cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine used as starting material can be prepared as follows:
Til 1000 g a-methyl-kanelaldehyd, 10 Ilter methanol og 789 g cis-2,6-dimethylmorpholin sættes under nitrogenatmosfære 50 g 5%'s palla-5 dium/kul. Der hydrogeneres derefter under køling med vand ved 30°C, indtil hydrogenoptagelsen er afsluttet, hvorefter katalysatoren frafiltreres, methanolet afdampes under reduceret tryk, og det rå cis-4-(2-methyl-3-phenylpropyl)-2,6-dimethylmorpholin destilleres. Det 99%'s rene produkt koger ved 109°C/0,055 mm Hg.To 1000 g of α-methyl-cinnamaldehyde, 10 L of methanol and 789 g of cis-2,6-dimethylmorpholine are added under nitrogen atmosphere to 50 g of 5% palladium / carbon. It is then hydrogenated under cooling with water at 30 ° C until the hydrogen uptake is completed, then the catalyst is filtered off, the methanol is evaporated under reduced pressure and the crude cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine is distilled. . The 99% pure product boils at 109 ° C / 0.055 mm Hg.
10 Eksempel 4.Example 4.
Til 20,0 g p-(a,a-dimethyl-benzyl)-a'-methyl-kanelaldehyd og 9,6 g cis-2,6-dimethylmorpholin i 60 ml methanol sættes under argonatmosfære 1 g 5%'s palladium/kui, hvorefter der hydrogeneres, indtil hydrogenoptagelsen er afsluttet. Reaktionsopløsningen befries for ka-15 talysator, inddampes under reduceret tryk, chromatograferes med chloroform på aluminiumoxid (aktivitetstrin II) og destilleres derefter i højvakuum. Der fås cis-4-(3-[p-(o,o-dimethyl-benzyl)phenyl]-2-meth-ylpropyl)-2,6-dimethylmorpholin med kogepunkt 162°C/0,04 mm Hg.To 20.0 g of p- (α, α-dimethyl-benzyl) -α'-methyl-cinnamaldehyde and 9.6 g of cis-2,6-dimethylmorpholine in 60 ml of methanol are added under argon atmosphere 1 g of 5% palladium / kui, then hydrogenated until the hydrogen uptake is completed. The reaction solution is freed from catalyst, evaporated under reduced pressure, chromatographed on chloroform on alumina (activity step II) and then distilled under high vacuum. Cis-4- (3- [p- (o, o-dimethyl-benzyl) phenyl] -2-methylpropyl) -2,6-dimethylmorpholine with boiling point 162 ° C / 0.04 mm Hg is obtained.
Eksempel 5.Example 5
20 Analogt med det i eksempel 4 beskrevne fås ved at gå ud fra p-(tert.amyl-phenyl)-a'-methyl-kanelaldehyd og cis-2,6-dimethylmor-. pholin ci$-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholin.Analogous to that described in Example 4 is obtained by starting from p- (tert-amyl-phenyl) -α'-methyl-cinnamaldehyde and cis-2,6-dimethylmor-. pholin ci $ -4- [3- (p-tert.amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine.
Eksempel 6.Example 6
25 Til en opløsning af 22,7 g 2,6-cis-dimethylmorpholin i 70 ml ethy-lenglycol dryppes langsomt ved 125°C 44,3 g 3-(p-tert.amyl-phen-yI)-2-methylpropylbromid, og der omrøres i 48 timer ved denne tem- 150509 η peratur. Efter afkøling tilsættes 2N saltsyre, og de neutrale dele eks-traheres med ether. Derefter indstilles den saltsure opløsning på alkalisk reaktion med 5N natriumhydroxidopløsning og ekstraheres med ether, og etherekstrakten vaskes med vand, tørres over natriumsulfat 5 og inddampes. Ved destillation fås rent cis-4-[3-(p-tert.amyl-phen-yl)-2-methylpropyl]-2,6-dimethylmorpholin, kogepunkt 120°C/0,1 mm Hg.To a solution of 22.7 g of 2,6-cis-dimethylmorpholine in 70 ml of ethylene glycol, drop slowly at 125 ° C 44.3 g of 3- (p-tert.amylphenyl) -2-methylpropyl bromide, and stirred for 48 hours at this temperature. After cooling, 2N hydrochloric acid is added and the neutral portions are extracted with ether. Then the hydrochloric acid solution is adjusted to alkaline reaction with 5N sodium hydroxide solution and extracted with ether and the ether extract is washed with water, dried over sodium sulfate 5 and evaporated. Distillation gives pure cis-4- [3- (p-tert.amyl-phenyl) -2-methylpropyl] -2,6-dimethylmorpholine, boiling point 120 ° C / 0.1 mm Hg.
Eksempel 7.Example 7
Til en opløsning af 22,7 g 2,6-cis-dimethylmorpholin i 80 ml ethy-10 lenglycol dryppes langsomt ved 125°C 51,8 g 3-[p-(o,a-dimethyl-ben-zyl)phenyl]-2-methylpropylbromid, og der omrøres i 48 timer ved denne temperatur. Oparbejdningen foretages analogt med eksempel 6.To a solution of 22.7 g of 2,6-cis-dimethylmorpholine in 80 ml of ethylene glycol, drop slowly at 125 ° C 51.8 g of 3- [p- (o, a-dimethylbenzyl) phenyl] -2-methylpropyl bromide and stirred for 48 hours at this temperature. The work-up is done analogously to Example 6.
Ved destillation fås rent cis-4-(3-[p-(a,a-dimethyl-benzyl)phenyl]-2'methylpropyl)-2,6-dimethylmorpholin, kogepunkt 162°C/0,04 mm Hg.Distillation gives pure cis-4- (3- [p- (a, a-dimethyl-benzyl) phenyl] -2'-methylpropyl) -2,6-dimethylmorpholine, boiling point 162 ° C / 0.04 mm Hg.
15 Eksempel 8.Example 8.
266 g cis-4-[3-(p-tert.amyl-phenyl)-2-methylpropyl]-2,6-dimethylmor-pholin opløses i 500 ml absolut ethanol og dryppes ved stuetemperatur til 500 ml af en 28%’s hydrogenchlorid-ethanolopløsning. Den homogene opløsning inddampes til tørhed på rotationsfordamper, og remanensen 20 omkrystalliseres af 100 ml vand. Krystallisatet vaskes med vand og tørres ved 55°C i vakuum tørreskab. Der fås hydrochloridet af cis- 4- [3- (p-tert. amyl-phenyl)-2-methylpropyl] -2,6-dimethylmorpholin i form af hvide, let hygroskopiske krystaller, smeltepunkt 204 - 206°C.266 g of cis-4- [3- (p-tert.amyl-phenyl) -2-methylpropyl] -2,6-dimethylmorpholine are dissolved in 500 ml of absolute ethanol and dropped at room temperature to 500 ml of a 28% hydrogen chloride-ethanol solution. The homogeneous solution is evaporated to dryness on a rotary evaporator and the residue 20 is recrystallized from 100 ml of water. The crystallate is washed with water and dried at 55 ° C in a vacuum drying cabinet. The hydrochloride of cis-4- [3- (p-tert. Amyl-phenyl) -2-methylpropyl] -2,6-dimethylmorpholine is obtained in the form of white, slightly hygroscopic crystals, mp 204-206 ° C.
Eksempel 9.Example 9
25 Til 21 g cis-4-[3-(p-tert.amyl-phenyl)-2-methylpropyl]-2,6-dimethyl-morpholin dryppes under acetone-tørisafkøling en opløsning af 60 ml 30%'s hydrogenperoxid i 60 ml eddikesyreanhydrid på en sådan måde, at reaktionstemperaturen ikke overstiger 50°C, hvorefter blandingenTo 21 g of cis-4- [3- (p-tert.amyl-phenyl) -2-methylpropyl] -2,6-dimethyl-morpholine is added dropwise under acetone-dry ice-cooling to a solution of 60 ml of 30% hydrogen peroxide in 60 ml. ml of acetic anhydride in such a way that the reaction temperature does not exceed 50 ° C, after which the mixture
Claims (3)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH756079 | 1979-08-17 | ||
| CH756079A CH644113A5 (en) | 1979-08-17 | 1979-08-17 | N-substituted 2,6-dimethylmorpholine compounds |
| CH418780 | 1980-05-29 | ||
| CH418780 | 1980-05-29 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK355180A DK355180A (en) | 1981-02-18 |
| DK150509B true DK150509B (en) | 1987-03-16 |
| DK150509C DK150509C (en) | 1987-10-12 |
Family
ID=25694874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK355180A DK150509C (en) | 1979-08-17 | 1980-08-15 | ANALOGY PROCEDURE FOR PREPARING CIS-4- (3-PHENYL-2-METHYL-PROPYL) -2,6-DIMETHYL MORPHOLINES |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP0024334B1 (en) |
| AR (1) | AR225318A1 (en) |
| AT (1) | ATE4206T1 (en) |
| AU (1) | AU530398B2 (en) |
| BG (1) | BG60798B2 (en) |
| CA (1) | CA1128943A (en) |
| CS (1) | CS402091A3 (en) |
| CU (1) | CU35298A (en) |
| DE (3) | DE3029966A1 (en) |
| DK (1) | DK150509C (en) |
| ES (2) | ES494314A0 (en) |
| FI (1) | FI69455C (en) |
| FR (1) | FR2463767B1 (en) |
| GB (1) | GB2056454B (en) |
| HR (1) | HRP930340B1 (en) |
| HU (1) | HU182189B (en) |
| IE (1) | IE52642B1 (en) |
| IL (1) | IL60813A (en) |
| IT (1) | IT1220970B (en) |
| LU (1) | LU82713A1 (en) |
| MC (1) | MC1345A1 (en) |
| MY (1) | MY8500272A (en) |
| NL (1) | NL8004537A (en) |
| NO (1) | NO153176C (en) |
| NZ (1) | NZ194628A (en) |
| PH (1) | PH15480A (en) |
| PT (1) | PT71708B (en) |
| SE (1) | SE447730B (en) |
| SI (1) | SI8011754A8 (en) |
| YU (1) | YU43475B (en) |
| ZW (1) | ZW15780A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3421810A1 (en) * | 1984-06-12 | 1985-12-12 | Basf Ag, 6700 Ludwigshafen | PHENYLALKYLAMINE - BIOREGULATORS |
| CA2008775C (en) * | 1989-02-24 | 1998-12-22 | Alberto Ferro | Nail lacquer |
| EP0446585A1 (en) * | 1990-03-12 | 1991-09-18 | F. Hoffmann-La Roche Ag | Control of fungal infections in aquaculture |
| EP1749825A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing amorolfine |
| EP1749826A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing bepromoline |
| EP1842848A1 (en) * | 2006-04-03 | 2007-10-10 | Galderma S.A. | Process for producing 3-[4-(1,1-dimethyl-propyl)-phenyl]2-methyl-propionaldehyde and cis-4{3-[4-(1,1-dimethyl-propyl)-phenyl]2-methyl-propyl}-2,6-dimethyl-morpholine (amorolfine) |
| EP1935889A1 (en) * | 2006-12-21 | 2008-06-25 | Galderma S.A. | Process of producing amorolfine |
| ITFI20090032A1 (en) | 2009-02-20 | 2010-08-21 | Synteco S P A Prodotti Di Sintesi Per L Ind | INDUSTRIAL PRODUCTION PROCESS OF CHLORIDATED AMOROLFIN |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT354187B (en) * | 1976-11-22 | 1979-12-27 | Hoffmann La Roche | FUNGICIDE AGENT |
| DE2656747C2 (en) * | 1976-12-15 | 1984-07-05 | Basf Ag, 6700 Ludwigshafen | Morpholine derivatives |
| ZA792242B (en) * | 1978-05-16 | 1980-05-28 | Hoffmann La Roche | Heterocyclic compounds |
| DE2830127A1 (en) * | 1978-07-08 | 1980-01-17 | Basf Ag | N-ARYL PROPYL SUBSTITUTED CYCLIC AMINES |
| DE2830999A1 (en) * | 1978-07-14 | 1980-01-31 | Basf Ag | METHOD FOR PRODUCING STEREOISOMERS N-ARALKYL-2,6-DIMETHYLMORPHOLINES |
| DE2965247D1 (en) * | 1978-08-08 | 1983-05-26 | Hoffmann La Roche | Synthesis of phenyl-propyl morpholine and piperidine derivatives |
| DE2907614A1 (en) * | 1979-02-27 | 1980-09-04 | Basf Ag | OPTICAL ACTIVE SHAPES OF THE 1- CORNER CLAMP ON 3- (P-TERT.-BUTHYLPHENYL) -2- METHYLPROPYL CORNER CLAMP ON -CIS-3,5- DIMETHYLMORPHOLINS |
-
1980
- 1980-07-07 ZW ZW157/80A patent/ZW15780A1/en unknown
- 1980-07-07 IT IT23283/80A patent/IT1220970B/en active
- 1980-07-08 YU YU1754/80A patent/YU43475B/en unknown
- 1980-07-08 SI SI8011754A patent/SI8011754A8/en unknown
- 1980-07-11 CA CA356,038A patent/CA1128943A/en not_active Expired
- 1980-07-25 AR AR281915A patent/AR225318A1/en active
- 1980-07-30 CU CU8035298A patent/CU35298A/en unknown
- 1980-08-01 FI FI802418A patent/FI69455C/en not_active IP Right Cessation
- 1980-08-05 PH PH24406A patent/PH15480A/en unknown
- 1980-08-07 EP EP80104656A patent/EP0024334B1/en not_active Expired
- 1980-08-07 DE DE19803029966 patent/DE3029966A1/en not_active Withdrawn
- 1980-08-07 AT AT80104656T patent/ATE4206T1/en active
- 1980-08-07 DE DE1993175077 patent/DE19375077I2/en active Active
- 1980-08-07 DE DE8080104656T patent/DE3064267D1/en not_active Expired
- 1980-08-08 NL NL8004537A patent/NL8004537A/en not_active Application Discontinuation
- 1980-08-11 AU AU61321/80A patent/AU530398B2/en not_active Expired
- 1980-08-11 NZ NZ194628A patent/NZ194628A/en unknown
- 1980-08-11 IL IL60813A patent/IL60813A/en unknown
- 1980-08-14 FR FR8017977A patent/FR2463767B1/en not_active Expired
- 1980-08-14 MC MC801466A patent/MC1345A1/en unknown
- 1980-08-14 LU LU82713A patent/LU82713A1/en unknown
- 1980-08-14 PT PT71708A patent/PT71708B/en unknown
- 1980-08-15 GB GB8026709A patent/GB2056454B/en not_active Expired
- 1980-08-15 HU HU802034A patent/HU182189B/en unknown
- 1980-08-15 NO NO802453A patent/NO153176C/en unknown
- 1980-08-15 IE IE1729/80A patent/IE52642B1/en not_active IP Right Cessation
- 1980-08-15 SE SE8005784A patent/SE447730B/en not_active IP Right Cessation
- 1980-08-15 DK DK355180A patent/DK150509C/en not_active IP Right Cessation
- 1980-08-16 ES ES494314A patent/ES494314A0/en active Granted
-
1981
- 1981-03-02 ES ES499957A patent/ES8201563A1/en not_active Expired
-
1985
- 1985-12-30 MY MY272/85A patent/MY8500272A/en unknown
-
1991
- 1991-12-23 CS CS914020A patent/CS402091A3/en unknown
-
1993
- 1993-03-12 HR HRP-1754/80A patent/HRP930340B1/en not_active IP Right Cessation
-
1994
- 1994-02-25 BG BG098580A patent/BG60798B2/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1107282A (en) | Process for the production of morpholine and piperidine derivatives and the products thereof | |
| US3963729A (en) | Pharmacologically active pyridine derivatives | |
| US5155220A (en) | Substituted isoxazolidines and isoxazolines as intermediates for delimopinal | |
| DK150509B (en) | ANALOGY PROCEDURE FOR PREPARING CIS-4- (3-PHENYL-2-METHYL-PROPYL) -2,6-DIMETHYL MORPHOLINES | |
| DE2711655C2 (en) | ||
| Cromwell et al. | Ethylenimine Ketones. XII. Stereoisomerism of 1-Cyclohexyl-2-(o-nitrophenyl)-3-benzoylethylenimine. Quinoline Syntheses | |
| US4216326A (en) | Intermediates for preparing anti-inflammatory phenyl-lower-alkylamines | |
| EP0008686A2 (en) | Synthesis of phenyl-propyl morpholine and piperidine derivatives | |
| US4387097A (en) | Morpholines | |
| US4474783A (en) | Cyclopropylmethyl piperazines, the process for preparing the same and their use in therapeutics | |
| Miller et al. | Optically active catecholimidazolines: a study of steric interactions at. alpha.-adrenoreceptors | |
| KR840001472B1 (en) | Process for preparing morpholine derivatives | |
| Sam et al. | Hypotensive Agents. Pyridinecarboxamides and Piperidinecarboxamides1 | |
| JPH01106860A (en) | N-substituted 3-aryl-pyrrolidine derivative, manufacture,fungicide and fungicidal method | |
| KR940009533B1 (en) | Process for preparing ammoniun salts derived from hexahydrodi-benzodioxane | |
| US3372161A (en) | Polycylicaminosulfones | |
| US2992222A (en) | Tetrahydrofurfurylpiperazines | |
| US3499892A (en) | Heterocyclic enamines of 5-norbornene-2-carboxaldehyde | |
| KR810000808B1 (en) | Process for preparing substituted quinolizidine and indolizidine derivatives | |
| US3856863A (en) | 4-p-({107 -aminoalkoxy)phenyl-1,2-diaryl-cyclopentanes and cyclopentenes | |
| EP0003316A2 (en) | Stereospecific process for the preparation of 2-oxiranyl-1,4-benzodioxanes | |
| EP0278265A1 (en) | 1- [(4-Morpholinyl) alkyl] -1H-indoles useful as analgesics and preparation thereof | |
| NO135707B (en) | ||
| JPS5936628B2 (en) | Production method of indazole derivatives | |
| Ellern | there is no need to do any, since whatever is of importance can be predicted a priori. It is, of course, typical of physical theory to |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| CTFF | Application for supplementary protection certificate (spc) filed |
Free format text: CA 1993 00044, 930629 |
|
| CTFF | Application for supplementary protection certificate (spc) filed |
Free format text: CA 1993 00044, 930629 |
|
| PUP | Patent expired |