DK142454B - Analogifremgangsmåde til fremstilling af antifibrillært aktive tetrahydronaphthyloxyaminopropanoler eller syreadditionssalte deraf. - Google Patents
Analogifremgangsmåde til fremstilling af antifibrillært aktive tetrahydronaphthyloxyaminopropanoler eller syreadditionssalte deraf. Download PDFInfo
- Publication number
- DK142454B DK142454B DK305571AA DK305571A DK142454B DK 142454 B DK142454 B DK 142454B DK 305571A A DK305571A A DK 305571AA DK 305571 A DK305571 A DK 305571A DK 142454 B DK142454 B DK 142454B
- Authority
- DK
- Denmark
- Prior art keywords
- tetrahydro
- propoxy
- hydroxy
- formula
- cis
- Prior art date
Links
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- 238000003756 stirring Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
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- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/36—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
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- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
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- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/17—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
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- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
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- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
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- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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Description
(11) FREMLÆGGELSESSKRIFT 142^5^ DANMARK (51) Int. Cl.3 C 07 C 93/06 UMINIVIMRIV C 07 D 303/26 §(21) Ansøgning nr. 5O55/7I (22) Indleveret den 21· jun. 19 Π (24) Løbedag 21 . jun. 1971 (44) Ansøgningen fremlagt og qoa fremlæggelsesskriftet offentliggjort den 2· HOV. 1 yoo
DIREKTORATET FOR
PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begæret fra den
22. jun. 1970, 48458, US
(71) E.R. SQUIBB & SONS INC., 909 Third Avenue, New York, N.Y. 10022, US.
(72) Opfinder: Frederic Peter Hauck, 12 Running Brook Rd., Sommerville, New Jersey, US: Christopher Michael Cimarusti, 4l6a Hamilton St., Somerset, New Jersey, US: Venkatachala Lakshmi Narayanan, 15 Covington Br., Hights^ town, New Jersey, US.
(74) Fuldmægtig under sagens behandling:
Ingeniørfirmaet Budde, Schou & Co.
(54) Analogifremgangsmåde til fremstilling af antifibrillært aktive tetra= hydronaphthyloxyaminopropanoler eller syreadditionBsalte deraf.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte tetrahydronanhthyloxvaminopro-panoler og med formlen
Η Η H R
0—C—C — C—IV
OH H XH
142454 2 hvori subs ti tuenterne Z og Z"*" er cis-stillede hydroxygrupper, eller Z og tilsammen danner en oxygenbro (>0) , og R betyder alkyl, der indeholder højst 8 carbonatomer, f.eks. methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, tert.butyl, isobutyl, n-pentyl, n--hexyl, isohexyl, n-heptyl, 4,4-dimethylpentyl, n-octyl og 2,2,4--trimethylpentyl, eller pharmakologiske acceptable syreadditionssalte deraf.
Forbindelserne med formlen I danner syreadditionssalte med uorganiske og organiske syrer. Disse syreadditionssalte er hyppigt anvendelige ved isolering af produkterne fra reaktionsblandingen ved saltdannelse i et middel, i hvilket saltet er uopløseligt. Den frie base kan derpå opnås ved neutralisation, f.eks. med en base, som f.eks. natriumhydroxid.
Derpå kan andre salte dannes ud fra den frie base med uorganiske eller organiske syrer. Til illustration heraf kan nævnes hydrohalogeniderne, især hydrochlorid og hydrobromid, som er de foretrukne, sulfat, nitrat, phosphat, borat, acetat, oxalat, tartrat, maleat, citrat, succinat, benzoat, ascorbat, salicylat, methansulfonat, benzensulfonat og toluensulfonat.
De ifølge opfindelsen fremstillede forbindelser er anti-fibrillære, dvs. aktive ved standsning af hjertearrhytmia i pattedyr, f.eks. ved inhibering af beta-adrenerge receptorer i hjertets muskulatur. Til dette formål kan en forbindelse med formlen I eller et physiologisk acceptabelt salt indgives på konventionel dosisform f.eks. som tabletter, kapsler, eliksir, injektioner eller lignende sammen med det nødvendige bærermateriale, excipiens, smøremiddel, puffer eller lignende. Enkelte eller opdelte dosiser på ca. 5 til ca. 25 mg/kg/dag, fortrinsvis ca. 4 til ca. 10 mg/kg en til fire gange daglig kan indgives i dosisform som beskrevet ovenfor.
Det er kendt, at l-naphthyloxy-2-propanol-3-alkylamino-forbindelser og specielt isopropylaminoforbindelsen har antifibril-lær aktivitet og den markedsføres som antiarrhytmika under NFN--navnet " Propanolol", normalt i form af hydrochloridet, der er anvendt som sammenligningsstof ved nedenstående biologiske afprøvning, hvoraf fremgår, at de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser er langt mere effektive og navnlig sikrere i brug.
Fra dansk patentskrift nr. 111.523 kendes l-alkylamino-3--(5,6,7,8-tetrahydro-l-naphthoxy)-2-propanoler, der angiveligt 3 U2454 har β-adrenergisk blokerende aktivitet og derfor er nyttige til behandling af coronararteriesygdom.
Specifikt beskrives kun tetrahydronaphthoxyforbindelser, som er usubstituerede i begge ringe; men ifølge de opregnede generiske betydninger i kravet i dansk patent nr. 111.523 kan den umættede ring være substitueret, f.eks. i 3- og/eller 4-stillingen, med halogen, hydroxy eller alkyl. Som sammenligningsgrundlag er derfor nu fremstillet sådanne repræsentative forbindelser, som indeholder en eller to hydroxygrupper i disse stillinger, da det er disse, som ligner de ved fremgangsmåden ifølge den foreliggende opfindelse mest i strukturel henseende.
Forskellen ligger i, at oxysubstituente(r)n(e) hos de "kendte" forbindelser sidder på den aromatiske ring, men hos de ifølge opfindelsen fremstillede sidder på den mættede ring (dvs. den alicycliske ring). Denne placering har afgørende betydning for aktiviteten, idet repræsentative kendte forbindelser og forbindelser fremstillet ifølge opfindelsen under ensartede betingelser er afprøvet for β-adrenergisk recpetor-blokerende aktivitet og for deres virkning på kontraktionskraften i ny-udopererede marsvinehjerte-forkammer-præparater. Herved konstateres, at det terapeutiske indeks DC10/IC50 (se nedenstående data) er 2-2000 gange så højt for de ifølge opfindelsen fremstillede forbindelser som for de kendte forbindelser. Førstnævnte er derfor sikrere i brug som betaadrenergisk receptor blokerende middel.
Forbindelserne med formlen I fremstilles ved fremgangsmåden ifølge opfindelsen, som karakteriseres ved, at man omsætter en forbindelse med formlen H n
0 —C—C-C-H
,:0°)11 1 " hvori Z og har den ovennævnte betydning, med en amin med formlen HN^
^R
hvori R har den ovennævnte betydning, og om ønsket omsætter den således dannede tetrahydronaphthyloxyaminopropanol med en hensigtsmæssig 4 142454 syre til frembringelse af pharmakologisk acceptable syreadditionssalte.
Udgangsmaterialer med formlen II, hvori Z og tilsammen er OC , fås ud fra α-naphthol med formlen
OH
C JL J 111 ved reduktion med et metal som f.eks. natrium eller lithium i flydende ammoniak indeholdende en alkanol med f.eks. ethanol, isopro-panol, tert.butanol eller lignende, f.eks. ved fremgangsmåden beskrevet i Organic Synthesis, Coll. Vol. 4 page 887 (1963), til opnåelse af 5,8-dihydronaphthol med formlen
OH
0Φ
Forbindelsen med formlen IV bringes til at reagere med et epoxid med formlen
H
Y— C — C --- C-H V
I I 1
HH H
hvori Y er chlor eller brom, til opnåelse af l-(2,3-epoxypropoxy)--5,8-dihydronaphthalen med formlen T ^
0—c—C-C-RH
ill I
H H H
l-(2,3-epoxypropoxy)-5,8-dihydronaphthalen omdannes derpå til den tilsvarende 1—(2,3-epoxypropoxy)-6,7-epoxy-5,6,7,8-tetrahydro-naphthalen med formlen 5 142654
ο—c —C-C-H
/3. Η Η H
<αζΧο| il· ved omsætning i et indifferent opløsningsmiddel som f.eks. methylen-dichlorid (CH2C12), med en organisk persyre som f.eks. m-chlorper-benzoesyre, perbenzoesyre, pernitrobenzoesyre eller pereddikesyre.
Den ønskede 1-[ (6,7-epoxy-5,6,7,8-tetrahydro-l-naphthyl)--oxy]-3-(substituerede amino)-2-propanol med formlen
O-C-C-C-N
R
hvori R er som ovenfor defineret, fås ved fremgangsmåden ifølge opfindelsen, f.eks. ved at koge tetrahydronaphthalenen under tilbagesvaling med en amin med formlen hn'
XR
hvori R er som anført i kravet, i et indifferent organisk opløsningsmiddel som f.eks. n-propanol, benzen eller toluen, f.eks. i ca. 16 til 24 timer. En alternativ fremgangsmåde medfører opvarmning af reagenserne i en Parr-tryk-reaktor ved en temperatur i området fra ca. 70 til ca. 110°C i 6 til 12 timer.
Forbindelser med formel I, hvori både Z og er hydroxy, dvs. 2,3-cis-l,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitueret amino)--propoxy]-2,3-naphthalendioler med formlen Η Η H J& O —C—C—C—
HO-^^VS « °H H R
6 142454 hvori R er som ovenfor defineret, fås ud fra de tilsvarende forbindelser med formel II, der selv fremstilles via en 5,8-dihydro-naphthol med formlen
OH
IV
ved omsætning med eddikesyreanhydrid og en organisk base som f.eks. pyridin til dannelse af det tilsvarende acetat med formlen 0
II
som opløses i eddikesyre og vand (fra 92% til 98% eddikesyre, fortrinsvis 96% eddikesyre), hvorpå opløsningen behandles med sølvacetat (ca. 2-4 ækvivalenter) og iod (ca. 1-2 ækvivalenter) ved opvarmning til 80-120°C under nitrogen i ca. 1 til ca. 24 timer efterfulgt af basisk hydrolyse til dannelse af 6,7-cis-5,6,7,8-tetrahydro--1,6,7-naphthalentriol med formlen
OH
efterfulgt af omsætning med epoxider med formlen V til 2,3-cis--1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalendiol, som omdannes til 2,3-cis-l,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitueret amino)-propoxy]-2,3-naphthalendiol ved fremgangsmåden ifølge opfindelsen.
De følgende eksempler tjener til illustrering af fremgangsmåden ifølge den foreliggende opfindelse: 7
U24SA
Eksempel 1 1-[(6,7-Epoxy-5,6,7,8-tetrahydro-l-naphthyl)-oxy]-3-(isopropylamino)--2-propanol___
Fremstilling af udgangsmateriale (a) 2,3-Epoxypropyl-6,7-epoxy-5,6,7,8-tetrahydro-l-naphtyletlier
Til en kraftig omrørt opløsning af 7 g (0,03 mol) 1-(2,3--epoxy-propoxy)-5,8-dihydro-naphthalen i 60 ml Ci^Clj, sættes dråbevis 7,1 g (0,03 mol) 85% m-chlorperbenzoesyre i 100 ml med en sådan hastighed, at temperaturen holdes mellem 25°C til 30°C. Blandingen omrøres natten over ved stuetemperatur. Bundfaldet (m-chlorbenzoesyre) frafiltreres, og Cl^Clj-ekstrakten vaskes derpå successivt med mættet NaHCO^-opløsning og vand. Efter tørring (MgSC>4) inddampes opløsningen i vakuum, hvilket giver 7,2 g <95%) olie, som størkner. En prøve omkrystalliseret efter ether giver hvide nåle, smeltepunkt 85-78°C: ^ 1330-1350 cm ^ (epoxy), i CDCl^ fravær af vinylprotoner i 4,0-4,2-dmrådet.
Analyse beregnet for C 71,54) H 6,47
Fundet C 71,50) H 6,77
Fremgangsmåden ifølge opfindelsen (b) 1-[(6,7-Epoxy-5,6,7,8-tetrahydro-l-naphtyi)-0xy]-3-(isopropyl- amino) -2-propanol_^\_r-·· _
En opløsning af 4,3 g (0,02 mol) 2,3-epoxypropyl-6,7-epoxy--5,6,7,8-tetrahydro-l-naphthylether i 34 ml (0,4 mol) isopropyl-amin anbringes i en lille Parr-bombe og opvarmes i et oliebad til ca. 70° - 80°C (tryk målt til 3,5 ato) i 10 timer. Afdampning af overskydende isopropylamin i vakuum giver et udbytte på 5,3 g af et brunt klæbrigt faststof. Krystallisation fra ether/pentan giver et udbytte på 2 g af et ikke rent hvidt faststof, smeltepunkt 106-110°C. En anden omkrystallisation fra ether giver et udbytte på 0,6 g af et hvidt faststof som første udbytte, smeltepunkt 115-117^,^ Nujol·, 3320 {m)' 1330-1350 cm"3- (epoxy), 'TCDCl.j 8,8-9,0 [-CH(CH3)2]
Analyse beregnet for C 69,28) H 8,36; N 5,05
Fundet: C69,43|H8,33> N 5,00 8 142454
Eksempel 2 2,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(tert.butylamino)-propoxy]- -2,3-naphthalendiol (a) 6,7-cis-5,6,7,3-Tetrahydro-l,6/7-naphthaientriol
En opløsning af 29,2 g (0,2 mol) 5,8-dihydro-l-naphthol og 40 ml eddikesyreanhydrid i 100 ml pyridin fremstilles. Efter 16 timers forløb fjernes opløsningsmidlet i vakuum, og remanensen opløses i ether og vaskes med 200 ml 5% saltsyre, vand, 200 ml 10% natriumhydroxid, mættet saltopløsning og tørres. Fjernelsen af opløsningsmidlet giver 43,2 g (90,5%) rå acetat, som opløses i 900 ml eddikesyre og 36 ml vand. 53,3 g (0,32 mol) sølvacetat tilsættes efterfulgt af 40,6 g (0,16 g-atom) iod. Opslæmningen opvarmes under god omrøring ved 85 - 10°C i 3 timer under nitrogen, afkøles og filtreres. Filtratet inddampes i vakuum, og remanensen opløses i 250 ml methanol og afkøles til 0°C. En opløsning af 40 g natriumhydroxid i 200 ml vand tilsættes under nitrogen, og blandingen omrøres natten over. Størstedelen af methanolet fjernes i vakuum, hvorefter der dannes et fast stof. Det faste stof skilles fra ved filtrering, opløses i 150 ml vand og gøres surt med 20 ml koncentreret saltsyre. Afkøling giver et fast stof, som filtreres og tørres, hvilket giver 16,5 g 6,7--cis-5,6,7,8-tetrahydro-l,6,7-naphthalentriol, smeltepunkt 184,5-187°C. Tre rekrystallisationer ud fra absolut ethanol giver den analytiske prøve, smeltepunkt 188-188,5°C.
Analyse: Beregnet for ^0^12^31 C 66,65, H 6,71.
Fundet: C 66,19, H 6,68.
(b) 2,3-cis-l,2,3,4-Tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalendiol
Der fremstilles en opløsning af 1,20 g (0,03 mol) natriumethoxid og 5,4 g (0,03 mol) 6,7-cis-5,6,7,8-tetrahydro-l,6,7-naphthalentriol i 200 ml methanol under nitrogen. Den fremkomne remanens ved fjernelse af opløsningsmidlet omrøres natten over med 200 ml dimethylsulfoxid og 4,65 g (0,05 mol) epichlorhydrin under nitrogen. Hovedparten af opløsningsmidlet fjernes ved 50°C ved 0,1 mm Hg og remanensen opløses i 100 ml vand. Ekstraktion med chloroform (10 x 200 ml) giver et fast stof, som rekrystalliseres ud fra 150 ml hexan/ethylacetat, hvilket giver 2,8 g af ovennævnte forbindelse, smp. 108-111,5°C.
(c) 2,3-cis-l,2,3,4-Tetrahydro-5-[2-hydroxy-3-(tert.butylamino)-propoxy] -2,3-naphthalendiol
En blanding af 3,0 g 2,3-cis-l,2,3,4-tetrahydro-5-[2,3-(epoxy)--propoxy]-2,3-naphthalendiol, smeltepunkt 104-107°C, (en plet på TLC på aluminiumoxid, 5% methanol i chloroform, fremkaldelse med iod) og 9 U2454 22 ml tert.butylamin opvarmes ved 85-95°C i 15 timer i en Parr bombe og overskydende amin fjernes i vakuum. Det fremkomne faste stof ved triturering af remanensen med ether filtreres og rekrystalliseres ud fra benzen, hvilket giver 3,4 g, smeltepunkt 124-136°C,
Analyse: Beregnet for ci7H27N04: C 65,99, H 8,80, N 4,53 Fundet: C 66,08, H 8,88, N 4,45.
Eksempel 3 2.3- cis-l,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylamino)-propoxy]- -2,3-naphthalendiol__
En opløsning af 2,75 g (0,011 mol) 2,3-cis-l,2,3,4-tetra-hydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalendiol fremstillet som beskrevet i eksempel 2a og b i 20 ml isopropylamin opvarmes ved 80 - 5°C i en Parr-bombe (overtryk = 2,8 kg/cm2) i 16 timer. Den overskydende amin fjernes i vakuum, og remanensen omkrystalliseres to gange fra 350 ml benzen til opnåelse af 2,32 g; smeltepunkt 112--120,5°C.
Analyse beregnet for C^H^NCy C 65,06) H 8,53; N 4,74 Fundet: C 65,27; H 8,65; N 4,61
Biologisk afprøvning
De nedenfor anførte forbindelser afprøves for beta-adre-nergisk receptor blokerende aktivitet og for deres kontraktile kraft på ny udopererede marsvinehjerte-forkammer-præparater ifølge den nedenfor specificerede fremgangsmåde med de i følgende tabel angive ne resultater, hvor forbindelserne har følgende strukturformler (rækkefølge som i tabellen) CH3 0-CHo-CH-CHo-N-C —-CH_ I 2 Ah 2 4 N:h3 3 HO^Cé 2.3- cis-l,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert.butylamino)propoxy]--2,3-naphthalendiol fremstillet ved fremgangsmåden ifølge opfindelsen (se eks. 2) .
10 142454 °η3 0-CHo-CH-CKL-N-C --CH, - °H *
OH
4-[2-hydroxy-3-{tert.butylamino)propoxy]-5,6,7,8-tetrahydro-l--naphthalenol, sammenligningsstof.
ch3 0-CH„ -CH-CH „ -N-C —-CH^ I 2 \ 2 I \ 3 oåOH H “3
T OH .CH-C00H
OH J
dl-4-[2-hydroxy-3-(tert.butylamino)propoxy]-5,6,7,8-tetrahydro-l,2--naphthalendiol, acetatsalt, sammenligningsstof.
/CH3 0-CHo-CH-CH--N-CH I 2 I 2 I \ 0H H ch-5
Zi lOl 2,3-cis-l,2,3,4-tetrahydro-5-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]-2,3-naphthalendiol fremstillet ifølge opfindelsen, (se eks. 3) .
/CH3 O-CH„-CH-CH 0-N-CH ^ I 2 I 2 I \ οφ ·
OH
4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-5,6,7,8-tetrahydro-l--naphthalenol, sammenligningsstof.
142454 11 CH- 3 O-CH^-CH-CH^-N-CH I 2 1 2 f \ I OH H ΧΉ- céx
.CH3COOH
OH
4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-5,6,7,8-tetrahydro-l,2--naphthalendiol, acetatsalt, saitimenligningsstof.
CH, / 3 0-CH0-CH-CHo-N-CH^ i Ah A \ch- @O] .HC1 1-(isopropylamino)-3-(1-naphthyloxy)-2-prqpanol, hydrochlorid. N)FN navn: "Propranolol", sammenligningsstof.
12 142454
Tabel IC50 DC10 DC10^
IC
Afprøvet forbindelse pg/ml pg/ml ^ 50 2.3- cis-l,2,3,4-tetra-hydro-5-[2-hydroxy-3--(tert-butylamino)pro-poxy]-2,3-naphthalendiol, (fremstillet iflg. 0,04 ^1.000 ^25.000 opfindelsen (eks. 2) 4-[2-hydroxy-3-(tert- -butylamino)propoxy]- -5,6,1,8-tetrahydro-l- -naphthalenol 0,01 rv 15 nJ1.500 dl-4-[2-hydroxy-3-(tert--butylamino)propoxy]--5,6,7,8-tetrahydro-l,2- -naphthalendiol, acetatsalt 0,1 rv 12 120 2.3- cis-l,2,3,4-tetra-hydro-5-[2-hydroxy-3- -[(1-methylethyl) amino]-propoxy]-2,3-naphthalendiol (fremstillet iflg. opfin., 0,1 > 1.000 >10.000 (eks. 3)).
4-[2-hydroxy-3-[(1-methyl-ethyl)amino]propoxy]-5,6,- 7.8- tetrahydro-l-naphthalenol 0,004 25 6.250 4-[2-hydroxy-3-[(1-methyl-ethy1) amino]propoxy]-5,6,- 7.8- tetrahydro-l,2-naphtha- lendiol,. acetatsalt 0,11 170 1.545 "Propranolol"-hydrochlorid 0,11 ^ 1,5 nj 13,6
Konklusion DCio/fcso forholdet for de afprøvede forbindelser viser, at de ifølge opfindelsen fremstillede 2,3-cis-l,2,3,4-tetrahydro-5--[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalendiol og 2,3-cis--1,2,3,4-tetrahydro-5-[2-hydroxy-3-((1-methylethyl)amino]propoxy]-2,3--naphthalendiol, er mere sikre at bruge som beta-adrenergiske receptor blokerende midler end de som sammenligningsstoffer afprøvede.
U 2454 13
Fremgangsmåde til bestemmelse af beba-adrenerq receptor-blokerende ' virkning og til bestemmelse af virkning på kontraktil kraft 1 forkammerpræparat udskåret af marsvin.
Hanmarsvin af Hartley-stammen med en vægt på 300-400 g hver aflives ved et slag nederst på kraniet. Brystkassen åbnes, og hjertet skæres hurtigt ud og anbringes i Feigan-opløsning ved stuetemperatur.
Feigan-opløsning gram/liter
NaCl - fysiologisk 9,0 KC1 - granullært 0,42
CaCl2 - vandfrit, 8 mesh 0,62
NaHCO^ ” pulver, United States
Pharmacopoeia 0,6
Dextrose - vandfrit, granullært 1,0
Opløsningen oxygeneres med en gasblanding af 95% 0^ og 5% C02 i mindst 10 minutter før brug.
Det ikke ønskede lungevæv og pericardiet skæres forsigtigt bort fra hjertet, så at atriet efterlades blottet til fjernelse. Det højre atrievedhæng bindes med kirurgisk sutur på den distale spids. En anden sutur bindes ved tilslutningen mellem vena caca superior og inferior, på en sådan måde, at sinusknuden forbliver intakt. Atriet skæres derefter bort fra ventriklen ved at skære langs basen af den højre ventrikel og gennem interatrie--skillevæggen, bindes til en vævsholder og anbringes i vandbad. Venstre forkammer fjernes på lignende måde med fastbindingerne anbragt ved de modsatte stænger på kanterne af atriet.
De anvendte vævsbade har et volumen på 10 ml og indeholder en til stadighed oxygeneret Feigan-opløsning (95% 02, 5% C02>, som holdes på 28°C ved hjælp af en cirkulationspumpe. Badene vaskes ud med frisk Feigan-opløsning hver 30 minutter undtagen under kumulativ præparatdosering.
Vævene forbindes med en "Grass FT.03" kraftforskydnings--transducer ved en hvilespænding på 1 g og får lov at komme i ligevægt en time før anvendelsen. De venstre forkamre stimuleres med en hyppighed på en gang pr. sekund af to platinelektroner, der daner et parallelt masivt felt, og som er forbundet med en "Tektronix" ®bølgegenerator, Serie 160. Den anvendte spænding er 1,5-2,0 gange større end tærsklen ved en pulsbredde på 5 millisekunder. De spontant bankende højre hjertekamre forbindes og 14 142454 bringes i ligevægt på samme måde uden anvendelse af stimulering. Resultaterne fra kraft-transducerne vises på en "Offner Dynograph" ® registrator. Den maksimale hastighed i spændingsudviklingen (dT/dt) fås ved elektronisk R-C-differentiering (tidskonstant = 0,075 sekunder) af spændingskurverne fra de drevne venstre forkamre.
Der indgives præparater til det elektrisk drevne venstre forkammervæv i stigende kumulative doser med 10 minutters mellemrum. Dosisvolumen er 0,1 ml, og dosisintervallet er kvadratroden af 10.
Der indgives Isoproterenol HCl, United States Pharmacopoeiea til det højre forkammervæv i doser, så at der opnås en endelig koncentration i badet på 0,003 jig/ml. Koncentrationsgraden optegnes 3 og 5 minutter efter indgivelse af præparatet. På dette tidspunkt vaskes præparatet ud af badet. Efter tilstrækkelig gentagelse af kontrolreaktionen, tilsættes en enkelt dosis af det beta-adrenerge blokerende præparat (dvs. prøveforbindelsen) til badet. Der tilsættes isoproterenol 25 minutter senere end prøveforbindelsen, og koncentrations-graden bestemmes igen 3 og 5 minutter senere (28 og 30 minutter efter indgivelse af prøveforbindelsen). ICj-q (den dosis af prøveforbindelsen, som hæmmer den tachykrotiske reaktion på isoproterenol med 50%) bestemmes grafisk.
De i ovenstående tabel anførte resultater angivet som IC,-0 er suppleret med oplysning om den koncentration af prøveforbindelsen, som frembringer 10%'s sænkning af spændingsfremkaldelsen, dvs. DC^q
Forholdet mellem DC1Q og IC5Q er det typiske terapeutiske indeks, som er afgørende for, om forbindelserne kan indgives med sikkerhed (risikofrit).
Til yderligere illustration af virkningen af repræsentative forbindelser fremstillet ved fremgangsmåden ifølge opfindelsen er følgende forbindelser afprøvet ved samme teknik som ovenfor angivet og med nedenstående resultat.
Beta-adrenergisk blokerende aktivitet In Vitro Atria-muskelprøve på marsvinehjerter
Forbindelse fremstillet ifølge eks. Styrke 2 1 3 0,4 1 2 142454 15
Styrken repræsenterer en sammenligning med den beta-adrener-giske blokerende aktivitet hos forbindelsen fremstillet ifølge eks. 2, idet denne aktivitet er sat til 1 (arbitrært valgt).
Applications Claiming Priority (2)
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US4845870A | 1970-06-22 | 1970-06-22 | |
US4845870 | 1970-06-22 |
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DK142454B true DK142454B (da) | 1980-11-03 |
DK142454C DK142454C (da) | 1981-03-30 |
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DK305571AA DK142454B (da) | 1970-06-22 | 1971-06-21 | Analogifremgangsmåde til fremstilling af antifibrillært aktive tetrahydronaphthyloxyaminopropanoler eller syreadditionssalte deraf. |
Country Status (13)
Country | Link |
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US (1) | US4156789A (da) |
JP (3) | JPS5038101B1 (da) |
AR (2) | AR198638A1 (da) |
CA (1) | CA979912A (da) |
CH (2) | CH548978A (da) |
DE (1) | DE2167224C3 (da) |
DK (1) | DK142454B (da) |
FR (1) | FR2100811B1 (da) |
GB (1) | GB1358721A (da) |
HK (1) | HK34379A (da) |
HU (1) | HU163633B (da) |
IE (1) | IE35375B1 (da) |
NL (2) | NL173268C (da) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
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US4241076A (en) * | 1978-02-21 | 1980-12-23 | E. R. Squibb & Sons, Inc. | Halogenated substituted mercaptoacylamino acids |
US4296110A (en) * | 1980-10-28 | 1981-10-20 | E. I. Du Pont De Nemours And Company | Antihypertensive I-substituted cyclic lactam-2-carboxylic acids |
US4402976A (en) * | 1981-04-24 | 1983-09-06 | E. R. Squibb & Sons, Inc. | Method for treating glaucoma with systemic nadolol compositions |
CA1249992A (en) * | 1983-11-10 | 1989-02-14 | Marcel Muller | Oxazolidines |
JPS60182880U (ja) * | 1984-05-17 | 1985-12-04 | 有限会社 金正陶器 | やじろべえ食器 |
JPS6364279U (da) * | 1986-10-17 | 1988-04-27 | ||
FR2648131B1 (fr) * | 1989-06-13 | 1991-10-18 | Oreal | Nouveaux derives de tetrahydro -5,6,7,8 naphtalenol-1, leur procede de preparation et leur utilisation en tant qu'agents antioxydants dans des compositions cosmetiques et pharmaceutiques les contenant |
CA1338717C (en) * | 1989-09-25 | 1996-11-12 | Khashayar Karimian | Nadolol |
US6587904B1 (en) | 1999-11-05 | 2003-07-01 | Apple Computer, Inc. | Method and apparatus for preventing loops in a full-duplex bus |
US7308517B1 (en) * | 2003-12-29 | 2007-12-11 | Apple Inc. | Gap count analysis for a high speed serialized bus |
CN104204165A (zh) * | 2012-03-21 | 2014-12-10 | 出光兴产株式会社 | 内燃机油用润滑油组合物 |
JP5876340B2 (ja) * | 2012-03-21 | 2016-03-02 | 出光興産株式会社 | 内燃機関油用潤滑油組成物 |
JP5876341B2 (ja) * | 2012-03-21 | 2016-03-02 | 出光興産株式会社 | 内燃機関油用潤滑油組成物 |
JP5876342B2 (ja) * | 2012-03-21 | 2016-03-02 | 出光興産株式会社 | 内燃機関油用潤滑油組成物 |
JP2016117788A (ja) * | 2014-12-18 | 2016-06-30 | Jxエネルギー株式会社 | 潤滑油添加剤、および潤滑油組成物 |
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US3367993A (en) * | 1965-08-09 | 1968-02-06 | Eastman Kodak Co | Polycarbonate elastomers from 5, 6, 7, 8-tetrahydro-1, 4-naphthalenediols |
DE2130393C3 (de) * | 1970-06-22 | 1981-02-26 | E.R. Squibb & Sons Inc., New York, N.Y. (V.St.A.) | 6,7-Dihydroxy -5,6,7,8-tetrahydronaphthyloxyaminopropanole und ihre Salze mit Säuren sowie ihre Verwendung bei der Bekämpfung von Herzerkrankungen |
US3906032A (en) * | 1972-11-10 | 1975-09-16 | Squibb & Sons Inc | Dihydroxy-tetrahydronaphthyoxyisobutyric acids and alkyl esters and salts thereof |
-
1971
- 1971-06-14 CA CA115,542A patent/CA979912A/en not_active Expired
- 1971-06-18 GB GB2873371A patent/GB1358721A/en not_active Expired
- 1971-06-18 IE IE791/71A patent/IE35375B1/xx unknown
- 1971-06-18 DE DE2167224A patent/DE2167224C3/de not_active Expired
- 1971-06-21 HU HUSU636A patent/HU163633B/hu unknown
- 1971-06-21 CH CH294273A patent/CH548978A/fr not_active IP Right Cessation
- 1971-06-21 DK DK305571AA patent/DK142454B/da not_active IP Right Cessation
- 1971-06-21 CH CH906771A patent/CH550770A/fr not_active IP Right Cessation
- 1971-06-22 NL NLAANVRAGE7108564,A patent/NL173268C/xx not_active IP Right Cessation
- 1971-06-22 FR FR7122694A patent/FR2100811B1/fr not_active Expired
- 1971-06-22 JP JP46045144A patent/JPS5038101B1/ja active Pending
-
1972
- 1972-10-30 AR AR244883A patent/AR198638A1/es active
- 1972-10-30 AR AR244884A patent/AR198639A1/es active
-
1975
- 1975-06-04 JP JP50068116A patent/JPS51125054A/ja active Granted
- 1975-10-09 US US05/620,980 patent/US4156789A/en not_active Expired - Lifetime
-
1978
- 1978-11-28 NL NL7811648A patent/NL7811648A/xx not_active Application Discontinuation
- 1978-12-25 JP JP16462878A patent/JPS54157550A/ja active Granted
-
1979
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Also Published As
Publication number | Publication date |
---|---|
CH548978A (fr) | 1974-05-15 |
NL7811648A (nl) | 1979-04-27 |
IE35375B1 (en) | 1976-01-21 |
DE2167224B2 (de) | 1981-07-09 |
JPS5038101B1 (da) | 1975-12-06 |
JPS54157550A (en) | 1979-12-12 |
GB1358721A (en) | 1974-07-03 |
NL173268C (nl) | 1984-01-02 |
JPS5649893B2 (da) | 1981-11-25 |
FR2100811B1 (da) | 1976-04-16 |
AR198638A1 (es) | 1974-07-15 |
DK142454C (da) | 1981-03-30 |
NL7108564A (da) | 1971-12-24 |
CH550770A (fr) | 1974-06-28 |
IE35375L (en) | 1971-12-22 |
DE2167224C3 (de) | 1982-03-25 |
JPS5747981B2 (da) | 1982-10-13 |
CA979912A (en) | 1975-12-16 |
FR2100811A1 (da) | 1972-03-24 |
HU163633B (da) | 1973-09-27 |
AR198639A1 (es) | 1974-07-15 |
US4156789A (en) | 1979-05-29 |
HK34379A (en) | 1979-06-01 |
JPS51125054A (en) | 1976-11-01 |
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