DK167011B1 - 4-(2,6,6-trimethylcyklohex-1-enyl)-but-3-en-1-ynylforbindelser og farmaceutiske praeparater indeholdende saadanne - Google Patents
4-(2,6,6-trimethylcyklohex-1-enyl)-but-3-en-1-ynylforbindelser og farmaceutiske praeparater indeholdende saadanne Download PDFInfo
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- DK167011B1 DK167011B1 DK682087A DK682087A DK167011B1 DK 167011 B1 DK167011 B1 DK 167011B1 DK 682087 A DK682087 A DK 682087A DK 682087 A DK682087 A DK 682087A DK 167011 B1 DK167011 B1 DK 167011B1
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Description
i DK 167011 B1
Den foreliggende opfindelse angår hidtil ukendte forbindelser med ret inoidl ignende aktivitet. Nærmere bestemt angår opfindelsen 4-(2,6,6-trimethylcykloh ex-1-e.nyl)-but-3-en-l-ynylfor-bindelser, hvori tre olefi nenheder fra den syrehold ige endeen-5 hed i retinsyre (vitamin A-syre) er erstattet af en ethynylhe-teroaromatiskho1 di g funktional itet. Sådanne modifikationer af ret insyrestrukturen har ret insyrelignende aktivitet. Opfindelsen angår desuden farmaceutiske præparater indeholdende disse forbindelser.
10
Nematocide forbindelser beskrevet i JP patentskrift nr. 56-123903 har strukturen 2-(2-((l,l-dimethyl)-dimethylsi lyl) -oxy) ethyl-a-(4-(2,6,6-trimethy1-1-cyklohexen-l-yl)-3-buten-l-ynyl)-l-cyklopenten-l-methanol. Denne forbindelse omfatter 15 1-(21,6',61-trimethy1cykl o-hex-1'-eny1)-but-l-en-3-yndelen af forbindelserne beskrevet heri. Dette fragment er imidlertid den eneste lighed mellem det japanske skrift og de forbindelser, der er beskrevet heri. Sådanne forbindelser er ikke genstand for den foreliggertde opfindelse.
20
Fra EP nr. 176.034 A2 kendes diarylacetylenforbindelser, som har virkning mod dermatose og arthritis. Det har nu overraskende vist sig, at også forbindelserne ifølge den foreliggende opfindelse har disse virkninger.
25
Forbindelserne ifølge den foreliggende opfindelse er ejendommelige ved den almene formel I
30 A-(CH2)n-B
35 hvor A er pyridindiyl, furandiyl eller thiophendiyl, n er 0-5, og B er -C0OH eller -COORi, hvor Rj er Ci_6-alkyl, eller -CONR2R2/ hvor hvert R2 uafhængigt er H eller Cj-ø-alkyl, eller farmaceutisk acceptable salte deraf.
2 DK 167011 B1
Forbindelserne ifølge opfindelsen kan anvendes til behandling af dermatosis, såsom acne, Darier's sygdom, psoriasis, i cthyθείε, eksem, atopisk dermatitis og epithel cancer. Disse forbindelser er også egnede ved behandling af arthritiske syg-5 domme og andre immunologiske forstyrrelser (f.eks. lupus erythematosus), til fremme af sårheling og til behandling af syndromet tørre øjne.
Den foreliggende opfindelse angår også et farmaceutisk præpa-10 rat omfattende en forbindelse med den almene formel I eller et farmaceutisk acceptabelt salt deraf i blanding med en farmaceutisk acceptabel excipiens.
Forbindelserne ifølge opfindelsen kan fremstilles ved omsæt-15 ning af en forbindelse med formel II med en forbindelse med formel III i nærværelse af Pd(PQ3)4 (Q er phenyl) eller et lignende kompleks.
x-a-<ch2>„-b
II III
25 hvor X er halogen, fortrinsvis I; og A, B og n er som ovenfor definere^ ti 1 opnåelse af en forbindelse med formlen I, eller homologisering af en forbindelse med formlen
-B
30 hvor n er 0-4, og A og B er som ovenfor defineret, eller om-35 dannelse af en syre med formel I til et syresalt, eller omdannelse af en syre med formel I til en ester eller omdannelse af en syre med formel I til et amid.
3 DK 167011 B1
Et farmaceutisk acceptabelt salt kan fremstilles af en hvilken som helst af forbindelserne ifølge opfindelsen med en evne til at danne sådanne salte, f.eks. en syre- eller en aminfunktio-nalitet. Farmaceutisk acceptabelt er et hvilket som helst 5 salt, som bevarer moderforbindelsens aktivitet, og ikke bevirker nogen som helst skadelig eller upassende virkning på det individ til hvilket det administreres og i den sammenhæng, i hvilken det administreres.
10 Farmaceutisk acceptable salte kan hidrøre fra organiske eller uorganiske syrer eller baser. Saltet kan være en mono- eller polyvalent ion. Af særlig interesse er de uorganiske ioner natrium, kalium, calcium og magnesium. Organiske salte kan fremstilles med aminer, især ammoniumsalte, såsom mono-, di-15 og trialkylaminer eller ethanolaminer. Salte kan også dannes med koffein, tromethamin og lignende molekyler.
De foretrukne forbindelser ifølge opfindelsen er de, hvor ethynylgruppen og B-gruppen er bundet til henholdsvis 2- og 20 5-stillingen i en pyridinring (6- og 3-stillingen i nikotin-syrenomenklaturen er ækvivalent til 2/5-betegnelsen i pyridin-nomenklaturen), eller henholdsvis 5- og 2-stillingen i en thiophengruppe, n er 0, 1 eller 2 og B er -C00H, et alkalimetalsalt eller organisk aminsalt eller en lavere alkylester 25 deraf. De mere foretrukne forbindelser er: ethyl-6-[4-(2,6,6-tri methyl cyklohex-l-eny1)-but-3-en-l-ynyl]-nikotinoat, 6-[4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-l-ynyl]nikotin-syre, 30 ethyl-5-[4-(2,6,6-tri methyl cykl ohex-1-eny1)-but-3-en-l-ynyl]- thiophen-2-carboxylat og 5-[4-(2,6,6-tri methyl cyklohex-l-eny1)-but-3-en-l-ynyl]thiophen- 2-carboxy1 syre.
35 Forbindelserne ifølge opfindelsen kan administreres systemisk eller topisk afhængigt af den tilstand, der skal behandles, behovet for stedspecifik behandling, mængde af lægemiddel, der skal administreres og adskillige andre forhold.
DK 167011 Bl 4
Ved behandlingen af dermatosis vil det generelt foretrækkes, at administrere lægemidlet topisk, selv om oral administration også kan anvendes i visse tilfælde, såsom ved behandling af alvorlig cystisk acne.
5
En hvilken som helst almindelig topisk formulering, såsom en opløsning, suspension, gel, salve eller balsam og lignende, kan anvendes til topisk behandling. Fremstilling af sådanne topiske formuleringer er velkendt og fuldstændigt beskrevet in-10 denfor området for farmaceutiske formuleringer, Som eksemple-ficeret af f.eks. Remington's Pharmaceutical Science, udgave 17, Mack Publishing Company, Easton, Pennsylvania. Til topisk applikation kunne disse forbindelser også indgives som et pulver eller i form af spray, især i aerosolform.
15
Hvis lægemidlet skal administreres systemisk, kan det sammensættes som et pulver, pille, tablet eller lignende, eller som en sirup eller eleksir til oral administration. Til intravenøs eller intraperi tonal administration vil forbindelsen blive in-20 darbejdet i en opløsning eller suspension, som er· i stand til at blive administreret ved injektion. I visse tilfælde kan det være hensigtsmæssigt at sammensætte disse forbindelser i suppositoriumform, eller som et præparat med forsinket frigivelse til deponering under huden eller ved intramuskulær injektion.
25
Andre medikamenter kan sættes til det topiske præparat for sekundære formål, som behandling af hudtørhed, tilvejebringelse af beskyttelse mod lys, andre medikamenter til behandling af dermatosis, forebyggelse af infektion, reduktion; af irrita-30 tion, inflammation og lignende.
Behandling af dermatosis eller hvilke som helst andre indikationer, som er kendte eller opdaget at være modtagelige for behandling af retinsyrelignende forbindelser, vil blive på-35 virket af administration af den terapeutiske effektive dosis af en eller flere forbindelser ifølge den foreliggende opfindelse.En terapeutisk koncentration vil være den koncentration, 5 DK 167011 B1 som bevirker svækkelse af den bestemte sygdom eller hæmmer dens udbredelse. I visse tilfælde kunne lægemidlet potentielt anvendes på profylaktisk måde for at modvirke begyndelse af en bestemt tilstand. En given terapeutisk koncentration vil vari-5 ere fra tilstand til tilstand, og kan i visse tilfælde variere alt efter alvorligheden af den tilstand, som behandles, og patienternes modtagelighed for behandling. En given terapeutisk koncentration vil derfor bedst bestemmes på det pågældende tidspunkt og sted gennem rutineeksperimentering.
10 '
Det forventes ved behandling af f.eks. acne eller andre sådanne hudlidelser, at et præparat indeholdende mellem 0,01 og 1,0 mg pr. ml præparat vil udgøre en terapeutisk effektiv koncentration. Hvis indgivet systemisk, ville en mængde på mellem 15 0,01 og 5 mg pr. kg legemsvægt pr. dag forventes at bevirke et terapeutisk resultat.
Den retinsyrelignende aktivitet af disse forbindelser blev bekræftet ved den klassiske måling af rétinsyreaktivitet, som 20 involverer virkningerne af retinsyre på ornithindecarboxylase.
Det oprindelige arbejde med korrelering mellem retinsyre og fald i celleproliteration blev gjort af Verma & Boutwell, Cancer Research, 1997, 37, 2196-2201. Denne reference beskriver, at ornithindecarboxylaseaktivitet (0DC) forøgedes forudgående 25 til polyaminbiosyntese. Det er blevet fastslået andetsteds, at forøgelse i polyaminsyntese kan korreleres eller forbindes med cellulær proliferation. Hvis; ODC-aktivitet kunne inhiberes, kunne cellehyperproliferation således moduleres. Selv om årsagerne til ODC-aktivitetsforøgelse er ukendt, er det kendt at 30 12-0-tetradecanoylphorbol-13-acetat (TPA) fremkalder ODC-akti - vitet. Retinsyre inhiberer denne fremkaldelse af ODC-aktivi tet af TPA. Forbindelserne ifølge opfindelsen inhiberer også TPA-fremkaldelse af ODC som vist ved hjælp af en analyse, som i alt væsentligt følger fremgangsmåden anført i Cancer Res.: 35 1662-1670, 1975.
Der blev således opnået følgende resultater ved analysen til bestemmelse af inhiberingen af TPA-induceret ornithindecarbo- 6 DK 167011 B1 xylaseaktivitet:
Forbindelse ODC-i nhi beringsanalyse, _IC80 (nmol)_ 5
Ethyl-6-[4-(2,6,6-trimethylcyklo- hex-l-enyl)-but-3-en-l-ynyl]nikotinoat 1,9 6-[4-(2,6,6-trimethylcyklohex-l-enyl)-10 but-3-en-*l-yny 1 ] nikoti nsyre 7,0 ethyl-5-[4-(2,6,6-trimethyl cyklohex-1-enyl)-but-3-en-l-yny1]thiophen-2-car-boxylat 30 15 5-[4-(2,6,6-tri methylcyklohex-1-eny1)- but-3-en-l-ynyl]-thiophen-2-carboxyl- syre 22 20 ethyl-5-[4-(2,6,6-trimethylcyklohex-l- enyl)-but-3-en-l-ynyl]furanoat >320
Det formodes, at forbindelserne ifølge opfindelsen kan fremstilles ad en række forskellige syntetiske, kemiske veje. For 25 at illustrere denne opfindelse, er en række trin, som har været anvendt til opnåelse af visse repræsentative forbindelser med formel I, vist i skema I. Syntesekemikeren kan let se, at de betingelser, der er anført i denne beskrivelse, er specifikke udføre!sesformer, som kan generaliseres til en hvilken 30 som helst.og alle af forbindelserne repræsenteret ved formel I.
Reaktionsskema I viser den generelle fremgangsmåde til fremstilling af forbindelserne med formel I.
35 7 DK 167011 B1
SKEMA I
δο^— 5 1 2 3
HALOGENSUBSTITUEREOE HETEROCYKLISKE
ESTERE / -i a-(Ch2)„-b l^i 4 SYRER, ESTERE, SALTE (n=0) \ / .A-(CH2)„-B n Λλ^ 20 \JL S SYRERf ESTERBr saLTE (n=l-5) 25 i dette skema kan halogenet i "halogen-substituerede, hetero-cykliske estere" være Br, Cl eller I, men Br og I foretrækkes.
A og B og n har den samme betydning som nævnt på side 2 under definitionen for substituenterne for forbindelsen med formlen I.
30
Anført generelt indføres den acetyleniske funktion ved behandling af ketonen med formel I med en stærk base og et dialkyl-chlorphosphat efterfulgt af basebehandling igen. Ved omdannelse af den acetyleniske gruppe til et tungmetalsalt, ZnCl-35 saltet, kan additionen af den acetyleniske funktion til en aromatisk ring derefter udføres. På grund af den basiske natur af dette ZnCl-salt, skal de sure egenskaber af B-gruppen mi- 8 DK 167011 B1 ni meres. Derivatisering af syrer er nødvend igt for at optimere reaktionsudbytter. Hvor det er nødvendigt at forlænge alkyl-kæden (-CH2)n") efter det foregående trin, kan dette udføres ved en homologiseringsreaktion, såsom Arndt-Eistert-reaktio-5 nen.
Forbindelser med formel 1 leveres af Aldrich Chemical Company under navnet j3-Ionone. Ketonen omdannes til en tripelbinding ved reduceret temperatur under en inert atmosfære ved hjælp af 10 1 i thiumdiisopropyl amid (LOA) eller en lignende base. Omsætnin gen udføres i et opløsningsmiddel af ethertypen, såsom dial-kylether eller et cyklisk ether, f.eks. tetrahydrofuran, pyran eller lignende.
15 Nærmere bestemt genereres 1ithiumdiisopropyl amid in si tu ved blanding af di isopropy1amin i et tørt opløsningsmiddel, såsom tetrahydrofuran, som derefter afkøles til mellem -70 og -50eC under en inert atmosfære. En ækvimolær mængde af en alkylli-thiumforbindelse, ' såsom n-butyllithium, i et passende opløs-20 ningsmiddel tilsættes derefter ved den reducerede temperatur, og der blandes i et passende tidsrum for at muliggøre dannelse af lithiumdiisopropylamid (LDA). Ketonen med formel 1 (mindst et 10% molært overskud) opløses i reaktionsopløsningsmidlet, opløsningen afkøles til temperaturen af LDA-blandingen og 25 sættes til denne opløsning. Efter kort blanding behandles opløsningen derefter med et dialkylchlorphosphat, fortrinsvis diethylchlorphosphat i ca. et 20% molært overskud. Reaktionsopløsningen bringes derefter gradvist til stuetemperatur. Denne opløsning tilsættes derefter til en anden 1ithiumdiiso-30 propylamidopløsning, som er fremstillet in situ under anvendelse af tørt opløsningsmiddel og under en inert atmosfære, fortrinsvis argon, ved reduceret temperatur (-78°C). Derefter opvarmes reaktionsblandingen igen til stuetemperatur, hvor den omrøres i et udstrakt tidsrum, fortrinsvis mellem 10 og 20 35 timer, mest foretrukket ca. 15 timer. Opløsningen syrnes derefter, og produktet udvindes ved hjælp af konventionelle separationsmidler.
DK 167011 Bl 9
Forbindelsen med formlen 3 fremstilles under betingelser, som udelukker al vand og oxygen. Et tørt opløsningsmiddel af ethertypen, såsom dialkylether eller en cyklisk ether, såsom furan eller pyran, især tetrahydrofuran, kan anvendes som op-5 løsningsmidlet. En opløsning af forbindelsen med formel 2 fremstilles først under en inert atmosfære, såsom argon eller nitrogen, og derefter tilsættes en stærk base, såsom n-butyl-lithium (i ca. et 10% molært overskud). Denne reaktion påbegyndes ved en reduceret temperatur på mellem -10°C og +10°C, 10 fortrinsvis ca. 0°C. Reaktionsblandingen om røres i et kort tidsrum mellem 30 min. og 2 timer, og behandles derefter med ca. et 10% molært overskud af smeltet zinkchlorid opløst i reaktionsopløsningsmidlet. Denne blanding omrøres i yderligere 1 til 3 timer ved ca. begyndelsestemperaturen, derefter forøges 15 temperaturen til ca. omgivelsernes temperatur i 10 til 40 min.
De halogensubstituerede, heterocykliske estere fremstilles ud fra deres tilsvarende syrer, idet halogenet er Cl, Br eller I. Disse pyridyl-, furyl- og thienylsyrer er alle tilgængelige 20 fra kemiske producenter, eller kan fremstilles ved hjælp af kendte metoder. Forestring udføres ved tilbagesvaling af syren i en opløsning bestående af en passende alkohol i nærværelse af thionylchlorid eller ved omsætning af syren og alkoholen i nærværelse af dicyklohexylcarbodiimid og dimethylaminopyridin. 25 Esteren udvindes og oprenses ved hjælp af konventionelle måder. Andre konventionelle metoder kan også anvendes til at foretage forestring.
For at udføre dannelse af forbindelsen med formel 4, opløses 30 ' alkylhalogenfuranoatet eller en tilsvarende al kyl halogenester af thiophen eller pyridin i et tørt opløsningsmiddel. Esteren anvendes i en mængde, som er ca. den molære mængde af udgangsmængden af forbindelsen med formlen 3. Denne opløsning indføres i en suspension af tetrakis(triphenylphosphin)pal 1 adium 35 (ca. en 5 til 10% molær mængde i forhold til reaktanterne) i reaktionsopløsningsmidlet ved en temperatur på mellem ca. -10°C og +10°C. Denne blanding omrøres kort i ca. 15 min. Til 10 DK 167011 B1 denne lige fremstillede blanding tilsættes derefter den i forvejen fremstillede opløsning af forbindelsen med formlen 3, zinkch1 or idsa1tet, idet tilsætningen foretages ved ca. stuetemperatur. Denne opløsning omrøres i en længere periode mel-5 lem ca. 15 og 25 timer ved stuetemperatur. Reaktionen stoppes derefter med syre, og produktet separeres fra og oprenses på konventionelle måder til opnåelse af forbindelserne med formlen 4.
20 Ved at tage esterne med formlen 4, forsæbe dem og derefter tage de resulterende syrer og underkaste dem på hinanden følgende Arndt-Eistert-homologiseringer, fås forbindelserne med formlen 5, hvor n er 1-5. Disse syrer kan derefter omdannes til estere med formlen I ved hjælp af fremgangsmåden beskrevet 25 ovenfor til forestring af de halogensubstituerede heterocykli-ske syrer.
Amid kan dannes ved hjælp af en hvilken som helst passende amideringsmåde, som er kendt indenfor området. I dette ti 1 -2o fælde er en måde at fremstille sådanne forbindelser først at fremstille syrechloridet, og derefter behandle denne forbindelse med ammoniumhydroxid. F.eks. behandles esteren med en alkoholisk base, såsom ethanolisk KOH (i ca. et 10% molært overskud) ved stuetemperatur i ca. \ time. Opløsningsmidlet 25 fjernes og resten tages op i et organisk opløsningsmiddel, såsom en ether, behandles med et dialkylformamid og derefter, et ti gange overskud af oxalylchlorid. Alt dette foregår ved reduceret temperatur på mellem ca. -10°C og +10°C. Den sidst-' nævnte opløsning omrøres derefter ved den reducerede tempera-1 30 tur i 1 til 4 timer, fortrinsvis 2 timer. Fjernelse af opløsningsmidlet efterlader en rest, som optages i et inert opløsningsmiddel, såsom benzen, afkølet til ca. 0°C, og behandles med koncentreret ammoniumhydroxid. Den resulterende blanding omrøres ved en reduceret temperatur i 1 til 4 timer. Produktet 35 udvindes på konventionelle måder.
Forbindelser, hvor B er -COOR2, fremstilles ud fra den tilsvarende halogen-heterocykli ske-enhed, fortrinsvis hvor halogenet 11 DK 167011 B1 er I. Denne halogenheterocykliske forbindelse omsættes med ethyny 1zinkchloridenheden, som beskrevet i reaktionsskema I, og mere specifikt i eksempel 3. Halog.ensubstituerede hetero-cykliske estere er kommercielt tilgængelige eller kan frem-5 stilles ved hjælp af metoder beskrevet i litteraturen.
De følgende eksempler er anført for at illustrere opfindelsen.
Eksempel 1 (fremstilling af udgangsmateriale) 10 l-(2,6,6-trimethvlcyklohex-l-envl)but-l-en-3-vn
En opløsning af 12,17 g (120,27 mmol) di isopropylamin i 200 ml tørt tetrahydrofuran blev afkølet til -78°C under argon og be-15 handlet dråbevis via en sprøjte med 75 ml 1,6 M (120 mmol) n-butyllithium i hexan. Denne blanding blev omrørt ved ca. -78°C i 1 time, og derefter behandlet via kanyle med en afkølet (-78*0) opløsning af 21,99 g (114,35 mmol) /3-ionon (1) i 20 ml tør tetrahydrofuran. Denne blanding blev omrørt ved ca. -78°C 20 i 1 time, behandlet dråbevis med 21,73 g (125,93 mmol) di-ethylchlorphosphat og fik lov til at opvarme til stuetemperatur i løbet af 2 timer. Denne opløsning blev derefter overført via kanyle til en opløsning af 1ithiumdiisopropylamid som var fremstillet ved omrøring under argon af en opløsning af 25 26,57 g (262,57 mmol) di isopropylamin i 150 ml tør tetrahydro- furan og 164 ml 1,6 M (262,4 mmol) n^butyll i thi um i hexan i 0,5 time ved -78°C. Blandingen fik lov til at opvarme til stuetempetur, blev omrørt i 15 timer, syrnet med 250 ml 3N HC1 og ekstraheret med pentan. Det organiske ekstrakt blev 30 vasket med IN HC1, vand, mættet NaHC03 og mættet NaCl og tørret (MgS04). Produktet blev koncentreret og destilleret 50*0, 0,1 mm) til opnåelse af forbindelsen nævnt i overskriften som en farveløs olie. PMR (CDCl3):6 1,0 (2CH3, s), 1,45 (2H, m), 1,65 (CH3, S), 1,92 (2H, m) 2,85 (IH, d, ->3Ηζ), 5,35 35 (IH, dd, J-16HZ, 3Hz), 6,6 (IH, d, J~16 Hz).
12 DK 167011 B1
Eksempel 2 (fremstilling af udgangsmateriale) Ethyl-6-chlornikotinoat 5 En blanding af 15,75 g (0,1 mol) 6-chlornikotinsyre, 5,9 g (0,15 mol) ethanol, 22,7 g (0,11 mol) dicyklohexy1carbodiimid og 3,7 g dimethylaminopyridin (0,03 mol) i 200 ml methylen-chlorid blev opvarmet ved tilbagesvaling i 2 timer. Blandingen fik lov til at afkøle, opløsningsmidlet blev fjernet i vakuum 10 og resten underkastet flashkromatografi til opnåelse af 16,7 g af den i overskriften nævnte forbindelse, som et lavtsmelten-de, hvidt fast stof.' PMR (CDC13): 6 1,44 (3H, t, J~ 6,2Hz), 4,44 (2H, q, J-4,4 Hz), 7,44 (IH, d, 8,1Hz), 8,27 (IH, dd, J~8,1Hz, 3Hz), 9,02 (IH, d, J-3Hz).
15
Eksempel 3
Ethyl-6-r4-(2,6,6-trimethyl cyklohex-l-enyl)-but-3-en-l-ynyl1-nikotinoat 20
Reaktionsbeholdere, der anvendes ved denne fremgangsmåde var flammetørrede under vakuum, og alle operationer blev udført i en oxygenfri argon- eller nitrogenatmosfære. Til en opløsning af forbindelsen beskrévet i eksempel 1, 602,7 mg (3,5614 mmol), 25 i 4 ml tørt tetrahydrofuran ved 0*0 blev dråbevis tilsat 2,25 ml 1,6 M (3,6 mmol) . n-butylli thium i hexan. Denne blanding blev omrørt ved 0°C i!10 min. ved stuetemperatur i 10 min. og afkølet igen til 0°C. Dertil blev sat via kanyle en opløsning af 500 mg (3,6689 mmol) smeltet zinkchlorid i 4 ml tør tetra-30 hydrofuran under omrøring ved 0°C i 1 time og ved stuetemperatur i 10 min. En opløsning af 664 mg (3,5774 mmol) ethyl-6-chlornikotinoat i 4 ml tørt tetrahydrofuran blev overført via kanyle til en suspension af 430 mg (0,3721 mmol) tetrakis(tri-phenylphosphin)palladium i 6 ml tørt tetrahydrofuran og omrørt 35 i 10 min. Denne blanding blev derefter behandlet via kanyle med opløsningen af alkynylzink og den resulterende blanding omrørt ved stuetemperatur i 60 timer. Vand blev tilsat (100 13 DK 167011 B1 ml) og produkterne ekstraheret med 3 x 100 ml ether. Forenede etherekstrakter blev vasket med mættet NaCl-opløsning, tørret (MgS04) og koncentreret til opnåelse af en brun olie. Denne olie blev oprenset ved hjælp af flashkromatografi (silicagel, 5 10¾ ethylacetat i hexaner) efterfulgt af højtryksvæskekromato grafi (Waters 6000, Partisil M-9 10/50, 5% ethylacetat i hexaner) til opnåelse af den i overskriften nævnte forbindelse, som en lysegul olie. PMR (CDC13), δ 1,06 (2CH3, s), 1,42 (3H, t, J - 7Hz), 1,46 (2H, m), 1,61 (2H, m), 1,78 (CH3, s), 2,05 10 (·2Η, m), 4,42 (2H, t, J~7Hz), 5,75 (IH, d, J~16,5Hz), 6,89 (IH, d, J - 16,5Hz) , 7,48 (IH, d, J-7,8Hz), 8,25 (IH, dd, J~7,8, "2 H z), 9,15 (IH, d, J~2Hz).
Ved at gå frem på lignende måde, men erstatte ethyl-6-chlorni-15 kotinoatet med den passende halogensubstituerede, heterocy-kliske ester blev de følgende forbindelser fremstillet: ethyl-2-[2-(4-(2,6,6-tr i methyl cyklohex-l-enyl)-but>-3-en-l-ynyl)- 5-pyridinyl]acetat, 20 ethyl-3-[2-(4-(2,6,6-trimethy1cyklohex-l-eny1)-but-3-en-l- ynyl)-5-pyridinyl]propionat, ethyl-4-[2-(4-(2,6,6-trimethy1 cyklohex-l-eny1)-but-3-en-l-ynyl)- 5-pyridinyl]butanoat, og ethy1-5-[2-(4-(2,6,6-trimethyl cyklohex-l-eny1)-but-3-en-l-ynyl)-25 5-pyridinyl]pentanoat.
Eksempel 4 (fremstilling af udgangsmateriale)
Ethyl- 5-brom-2-furoat 30
Til en omrørt suspension af 8,43 g (44,14 mmol) 5-brom-2-fu-ronsyre i 100 ml absolut ethanol blev sat 4 ml thionylchlorid. Denne blanding blev omrørt under tilbagesvaling i 3 timer og ved stuetemperatur i 18 timer. Opløsningsmidlet blev fjernet i 35 vakuum, den tilbageværende olie behandlet med 100 ml vand og ekstraheret med 3 x 75 ml ether. De forenede etherekstrakter blev vasket med mættet NaHCOø- og mættet NaCl-opløsninger og DK 167011 Bl 11 tørret (MgSO^j). Opløsningsmidlet blev fjernet i vakuum og resten destilleret (60°C, 0,4 mm) til opnåelse af den i overskriften nævnte forbindelse som en farveløs olie- PMR (CDC13): δ 1,35 (3H, t, J - 7HZ), 4,37 (2H, q, J~ 7Hz), 6,45 (IH, d, 5 J~4Hz), 7,1 (IH, d, J~4Hz).
Eksempel 5 (fremstilling af udgangsmateriale) 10 Ethyl-5-bromthiophen-2-carboxylat
Til 1,092 g (5,7157 mmol) 5-bromthiophen-2-carboxa1dehyd blev sat i rækkefølge 1,507 g (30,75 mmol) natriumcyanid, 60 ml ethanol, 602,5 mg (10,04 mmol) eddikesyre og 10,62 g (122,16 15 mmol) mangandioxid. Denne blanding blev omrørt ved stuetemperatur i 24 timer, derefter filtreret gennem celit og resten vasket flere gange med ether. De forenede filtrater blev koncentreret, derefter blev restep taget op i vand og ekstraheret med 3 x 75 ml ether. Forenede etherekstrakter blev vasket med 20 mættet NaHC03, mættet NaCl, tørret (MgSO^), inddampet i vakuum og destilleret (70°C, 0,1 mm) til opnåelse af den i overskriften nævnte forbindelse som en lysegul olie. PMR (CDC^): 6 1,3 (3H, t, J-7Hz), 4,35 (2H, t, J~7Hz), 7,12 (IH, d, >4Hz), 7,6 (IH, d, J~4Hz) .
25
Eksempel 6
Ethvl-5-r4-(2,6,6-trimethvl-cyklohex-l-env1)-but-3-en-l-vnvn- 2-furoat 30 Ethvl-5-r4-(2,6,6-tr i methyl -cy'k 1 ohex-l-enyl )-but-3-en-l-ynyll- thiophen-2-carboxyl at
Ved anvendelse af fremgangsmåden og betingelserne beskrevet i eksempel 3, men ved at anvende henholdsvis ethyl-5-brom-2-fu-35 roat, som var fremstillet i eksempel 4, eller ethyl-5-brom-thiophen-2-carboxylat, som var fremstillet i eksempel 5, i stedet for ethyl-6-chlor-nikotinoat, blev de i overskriften nævnte DK 167011 B1 15 forbindelser fremstillet. Furoatet havde de følgende PMR spek-trale karakteristika: PMR (CDC13) : δ 1,1 (6H, s), 1,43 (3H,t, J - 7,6Hz) , 1,52 (2H, m), 1,65 (2H,. m), 1,81 (3H, 3), 2,1
(2H, m), 4,42 (2H, q, J~7,6Hz), 5,73 (IH, d, J~16,8Hz), 6,66 5 (IH, d, J ~ 3,5Hz) , 6,83 (IH, d, J~16,8Hz), 7,21 (IH, d, J
~ 3,5Hz). Thiophen-2-carboxylatforbindelsen havde de følgende PMR spektrale karakteristika: PMR (CDCI3): δ 1,08 (6H, s), 1,39 (3H, t, J ~ 7,2Hz), 1,50 (2H, m), 1,62 (2H, m), 1,79 (3H, s), 2,08 (2H, m), 4,37 (2H, q, J ~ 7,5Hz), 5,72 (IH, d, J 10 “ 16,5Hz), 6,76 (IH, d, J~16,5Hz), 7,14 (IH, d, >3,9Hz), 7,67 (IH, d, J~3,9Hz).
Ved at gå frem på lignende måde, men erstatte ethyl-thiophen-2-carboxylat og ethyl-5-brom-2-furoat med den passende hetero-15 cykliske ester blev de følgende forbindelser fremstillet: ethyl-2-[5-(4-(2,6,6-trimethylcyklo-hexenyl)-but-3-en-l-ynyl)-fur-2~y1]acetat, ethyl-3-[5-(4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-l-ynyl)- fur-2-yl]propionat, 20 ethyl-4-[5-(4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-l-ynyl)“ fur-2-yl]butanot, ethyl-5-[5-(4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-l-yny1)-fur-2-yl]pentanoat, ethyl-2-[5-(4-(2,6,6-tri methyl cyklohex-l-eny1)-but-3-en-l-yny1)-25 thiophen-2-yl]acetat, ethyl-3-[5-(4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-l-ynyl)- thiophen-2-yl]propionat, ethyl-4-[5-(4-(2,6,6-tri methyl cyklohex-l-eny1)-but-3-en-l-ynyl)-thiophen-2-yl]butanoat, og 30 ethyl-5-[5-(4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-l-yny1)- thiophen-2-yl]pentanoat.
35
Claims (5)
- 5 Nitrogengas blev boblet gennem de ved dette forsøg anvendte opløsninger umiddelbart før anvendelse. Til en omrørt opløsning af 53 mg (0,1641 mmol) ethyl-6-[4-(2,6,6-trimethylcyklo-hex-l-enyl)but-3-en-l-ynyl]nikotinoat i 200 ml ethanol blev der under nitrogen sat 132 ml af en 1,86 M (0,2459 mmol) op-10 løsning af Κ0Η i ethanol og vand. Efter omrøring ved stuetemperatur i 3 timer blev opløsningsmidlet fjernet i vakuum og resten behandlet med 1 ml vand og ekstraheret med 2 x 1 ml portioner af ether. De vandige lag blev derefter syrnet med 50% vandig eddikesyre og ekstraheret med 3 x 2 ml ether. For-15 enede etherekstrakter blev tørret (MgSO^ og inddampet i vakuum til opnåelse af den i overskriften nævnte forbindelse som et lysegult pulver. PMR (00013): δ 1,06 (6H, s), 1/48 (2H, m), 1,62 (2H, m) 1,78 (3H, s), 2,05 (2H, m), 5,75 (IH, d, 3-16,4Hz), 6,93 (IH, d, 3- 16,4Hzj, 7,55 (IH, d, 3-8,1Hz), 8,35 (IH, dd, 20 3-8,1, 2,3Hz) , 9,29 (IH, d, 3-2,3Hz). Ved at gå frem på samme måde kan estere fremstillet efter ek sempel 6 omdannes til den tilsvarende syre. F.eks.: 5-[4-(2,6,6-tri methy1-cyklohex-l-eny1)-but-3-en-l-yny1]furan-25 syre, og 5-[4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-l-ynyl]thiophen- 2-carboxylsyre. Patentkrav. 30 ---------------------- 1. 4-(2,6,6-tri methyl cyklohex-l-enyl)-but-3-en-l-yny1 forbin delse, kendetegnet ved den almene formel 35 DK 167011 B1 XvXAKCH!)'-b 5 hvor A er pyridindiyl, furandiyl eller thiophendiyl, n er 0-5 og B er -C00H eller -COORi, hvor Rj er Ci-6alkyl, eller -CONR2R2/ hvor hvert R2 uafhængigt er H eller Ci-6alkyl, eller et farma-10 ceutisk acceptabelt saltderaf.
- 2. Forbindelse ifølge krav 1, kendetegnet ved, at A er pyridindiyl, B er -C00H eller -COORi, hvor Ri er Ci-gal-kyl, eller et farmaceutisk acceptabelt salt deraf. 15
- 3. Forbindelse ifølge krav 2, kendetegnet ved, at den er ethy1-6-[4-(2,6,6-trimethylcyklohex-l-enyl)-but-3-en-1-ynyl]nikotinoat eller 6-[4-(2,6,6-tri methyl cyklohex-l-enyl)-but-3-en-l-yny1]ni kotin-20 syre eller et farmaceutisk acceptabelt salt deraf.
- 4. Forbindelse ifølge krav 1, kendetegnet ved, at A er furandiyl, og B er -C00H eller -COORi, hvor Ri er Ci-6al-kyl, eller et farmaceutisk acceptabelt salt deraf. 255. Forbindelse ifølge krav 4, kendetegnet ved, at den er ethy1-5-[4-(2,6,6-1rimethyl cyklohex-l-enyl)-but-3-en-1-ynyl]furanoat eller et farmaceutisk acceptabelt salt deraf.6. Forbindelse ifølge krav 1, kendetegnet ved, at A er thiophendiyl, B er -C00H eller -COORi, hvor Ri er Ci-eal--'"' kyl, eller et farmaceutisk acceptabelt salt deraf. 1 Forbindelse ifølge krav 6, kendetegnet ved, at 35 den er ethyl-5-[4-(2,6,6-trimethylcyklohex-1-enyl)-but-3-en-l-ynyl]thiophen-2-carboxylat eller 5-[4-(2,6,6-trimethylcyklo-hex-l-enyl)-but-3-en-l-ynyl]-thiophen-2-carboxylsyre. DK 167011 B18. Farmaceutisk præparat, kendetegnet ved, at det omfatter en farmaceutisk acceptabel excipiens og en forbindelse med formlen
- 5 A-(CH2)n-B T 10 hvori A er pyridindiyl, furandiyl ;eller thiophendiyl, n er 0-5 og B er -C00H eller -COOR^, hvor er Ci-øalkyl, eller -CONR2R2/ hvor hvert R2 uafhængigt er H eller Ci-øalkyl, eller et farmaceutisk acceptabelt salt deraf. 15 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US94674986A | 1986-12-24 | 1986-12-24 | |
| US94674986 | 1986-12-24 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK682087D0 DK682087D0 (da) | 1987-12-22 |
| DK682087A DK682087A (da) | 1988-06-25 |
| DK167011B1 true DK167011B1 (da) | 1993-08-16 |
Family
ID=25484939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK682087A DK167011B1 (da) | 1986-12-24 | 1987-12-22 | 4-(2,6,6-trimethylcyklohex-1-enyl)-but-3-en-1-ynylforbindelser og farmaceutiske praeparater indeholdende saadanne |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0272921B1 (da) |
| JP (1) | JP2693957B2 (da) |
| KR (1) | KR960000074B1 (da) |
| CN (1) | CN1024006C (da) |
| AT (1) | ATE62899T1 (da) |
| AU (1) | AU599444B2 (da) |
| CA (1) | CA1326853C (da) |
| DE (1) | DE3769618D1 (da) |
| DK (1) | DK167011B1 (da) |
| EG (1) | EG19587A (da) |
| ES (1) | ES2036591T3 (da) |
| FI (1) | FI90766C (da) |
| GR (1) | GR3002101T3 (da) |
| HU (1) | HU198295B (da) |
| IE (1) | IE61902B1 (da) |
| IL (1) | IL84878A (da) |
| MY (1) | MY103040A (da) |
| NO (1) | NO175205C (da) |
| NZ (1) | NZ222968A (da) |
| PH (1) | PH23861A (da) |
| PT (1) | PT86442B (da) |
| ZA (1) | ZA879595B (da) |
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| US5264456A (en) * | 1989-12-29 | 1993-11-23 | Allergan, Inc. | Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity |
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| JP3499553B2 (ja) * | 1992-02-11 | 2004-02-23 | アラーガン、インコーポレイテッド | レチノイド様生物学的活性を有するヘテロアリール置換フェニルエテニル化合物 |
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| US6166244A (en) * | 1999-05-07 | 2000-12-26 | Allergan Sales, Inc. | Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity |
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| EP1224168B1 (en) * | 1999-10-07 | 2006-08-09 | Phytera, Inc. | Antifungal enediynes |
| CN106632175A (zh) * | 2016-11-23 | 2017-05-10 | 山东友帮生化科技有限公司 | 5‑溴‑2‑糠酸乙酯的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2065014A1 (de) * | 1969-05-14 | 1971-12-09 | Sumitomo Chemical Co. Ltd., Osaka (Japan) | S-Propargyl-2- oder -3-thenylalkohole und Verfahren zu ihrer Herstellung. Ausscheidung aus: 2015869 |
| DE3338846A1 (de) * | 1982-10-29 | 1984-05-03 | Toyama Chemical Co. Ltd., Tokyo | Neue 4-oxo-1,4-dihydronicotinsaeurederivate und salze derselben, verfahren zu ihrer herstellung und antibakterielle mittel mit einem gehalt derselben |
| DE3434946A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Diarylacetylene, ihre herstellung und verwendung |
-
1987
- 1987-12-17 NZ NZ222968A patent/NZ222968A/xx unknown
- 1987-12-18 CA CA000554751A patent/CA1326853C/en not_active Expired - Fee Related
- 1987-12-18 MY MYPI87003218A patent/MY103040A/en unknown
- 1987-12-18 PH PH36269A patent/PH23861A/en unknown
- 1987-12-21 IL IL84878A patent/IL84878A/xx not_active IP Right Cessation
- 1987-12-22 ZA ZA879595A patent/ZA879595B/xx unknown
- 1987-12-22 DE DE8787311318T patent/DE3769618D1/de not_active Expired - Fee Related
- 1987-12-22 FI FI875681A patent/FI90766C/fi not_active IP Right Cessation
- 1987-12-22 IE IE349387A patent/IE61902B1/en not_active IP Right Cessation
- 1987-12-22 EP EP87311318A patent/EP0272921B1/en not_active Expired - Lifetime
- 1987-12-22 AT AT87311318T patent/ATE62899T1/de not_active IP Right Cessation
- 1987-12-22 DK DK682087A patent/DK167011B1/da not_active IP Right Cessation
- 1987-12-22 PT PT86442A patent/PT86442B/pt not_active IP Right Cessation
- 1987-12-22 ES ES198787311318T patent/ES2036591T3/es not_active Expired - Lifetime
- 1987-12-22 AU AU82925/87A patent/AU599444B2/en not_active Ceased
- 1987-12-22 HU HU875956A patent/HU198295B/hu not_active IP Right Cessation
- 1987-12-23 NO NO875422A patent/NO175205C/no unknown
- 1987-12-23 EG EG74287A patent/EG19587A/xx active
- 1987-12-23 KR KR1019870014758A patent/KR960000074B1/ko not_active IP Right Cessation
- 1987-12-23 CN CN87107535A patent/CN1024006C/zh not_active Expired - Fee Related
- 1987-12-24 JP JP62336783A patent/JP2693957B2/ja not_active Expired - Lifetime
-
1991
- 1991-06-10 GR GR91400780T patent/GR3002101T3/el unknown
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Legal Events
| Date | Code | Title | Description |
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| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |