WO1997011067A1 - Fluorophores a liaison polymere utilises en tant que capteurs optiques d'ions - Google Patents

Fluorophores a liaison polymere utilises en tant que capteurs optiques d'ions Download PDF

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Publication number
WO1997011067A1
WO1997011067A1 PCT/EP1996/003954 EP9603954W WO9711067A1 WO 1997011067 A1 WO1997011067 A1 WO 1997011067A1 EP 9603954 W EP9603954 W EP 9603954W WO 9711067 A1 WO9711067 A1 WO 9711067A1
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formula
weight
polymer
copolymer according
ila
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PCT/EP1996/003954
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English (en)
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Alex Alder
Steven Mark Barnard
Dirk Beckelmann
Joseph Berger
Adrian Waldner
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Novartis Ag
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Priority to AU69888/96A priority Critical patent/AU6988896A/en
Priority to JP9512206A priority patent/JP2000501069A/ja
Priority to EP96931059A priority patent/EP0876363A1/fr
Publication of WO1997011067A1 publication Critical patent/WO1997011067A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/533—Production of labelled immunochemicals with fluorescent label

Definitions

  • the present invention relates to functionalised rhodamines and acridines, to processes for their preparation as well as to polyacrylates, polymethacrylates and polyurethanes which contain these rhodamines or acridines bound covalently via their functional groups.
  • the invention also relates a) to an optical sensor, comprising the polymer-bound fluorophores, counterions in the form of lipophilic salts and a ionophore, b) to a process for the optical determination of ions by the fluorescence method, e.g. of cations selected from the group consisting of metal cations and ammonium cations, or e.g. of anions selected from the group consisting of anions of inorganic or organic acids, and also c) to the use of the optical sensor for the determination of anions or cations, in particular in aqueous solutions.
  • an optical sensor comprising the polymer-bound fluorophores, counterions in the form of lipophilic salts
  • the sensors which are also termed optrodes, usually consist of a transparent carrier material and an active layer.
  • Said active layer normally comprises a transparent hydrophobic polymer and a lipophilic plasticiser to achieve sufficient diffusion of the ions and solubility of the active components.
  • Active components are a specific ionophore as sequestrant for ions, a counterion to maintain the electric neutrality and an indicator substance which produces a measurable optical signal resulting from a chemical or physical change of the environment.
  • US-A-4 645 744 describes such systems wherein the indicator substance is a neutral compound such as a dye (p-nitrophenol) which interacts with a ionophore/metal cation complex resulting in an optically measurable signal in the form of a change in colour.
  • the interaction can, for example, cause the removal of a proton from a dye resulting in a change of the electron state.
  • Fluorescent compounds e.g. fluorescein
  • fluorescein are also cited as suitable, the fluorescence of which can be altered by the change in the electron state and can be optically determined via fluorescence measurements.
  • H. He et al. describe systems using a proton carrier (nile blue) as indicator substance, in which systems the transport of potassium into the active layer using valinomycin as ionophore dissociates the proton carrier and one proton diffuses into the aqueous phase.
  • the proton carrier changes its colour from blue to red and, depending on the chosen wavelength, it is possible to determine the decrease in fluorescence of the blue dye or the corresponding increase in fluorescence of the red dye. Owing to higher sensitivity and selectivity, it is preferred to measure the fluorescence.
  • One substantial disadvantage of the process is the low sensitivity of the system which is due to the low quantum yield of fluorescence of the indicator dye employed.
  • Y. Kawabata describes a membrane system for the optical determination of potassium which is based on the use of a hydrophobic ion exchanger, namely 3,6-bis(dimethylamino)-10-dodecyl-acridinium bromide or 3,6-bis(dimethylamino)-10-dodecyl-10-hexadecyl-acridinium bromide.
  • a change in fluorescence is achieved by changing the polarity of the microenvironment of the sample because the acridinium salts diffuse via ion exchange with the potassium ion to the interface of the aqueous phase.
  • the systems commonly known today comprise in the active layer high molecular weight hydrophobic polymers (typically PVC) in combination with a plasticiser to ensure fast response times and sufficient sensitivities.
  • a plasticiser typically PVC
  • long-term stability and repeated use is severely restricted because the plasticiser and other low molecular weight components such as ionophores or fluorophores are washed out in the course of time.
  • the state of the art tries to solve the long-term stability problem of the optical sensor by introducing highly lipophilic groups into the components employed.
  • acridine and rhodamine dyes are lipophilic, pH- sensitive as well as strongly basic fluorophores which are excellently suited for use in a neutral plasticiser-free polymer membrane of low glass transition temperature T g together with a ionophore and a counterion for determining ions according to the ion exchange mechanism.
  • the fluorophores are distinguished by a high quantum yield of fluorescence, high basicity, a great difference between the fluorescence signals of the protonated and deprotonated form, high lipophilic properties, sufficient photostability and suitable abso ⁇ tion and emission wavelengths. It is possible to fabricate highly sensitive systems for the optical determination of ions based on fluorescence measurements.
  • the polymers in the membrane can be plasticiser-free hydrophobic polymers having a defined low glass transition range and because no washing-out of the fluorophores need be feared. This is a special advantage in particular in very thin membranes having fast response times.
  • the invention relates to compounds of formula I, Ila or lib
  • Ri, R 2 , Rs and R 6 are each independently of one another hydrogen, -SO 2 -(C ⁇ -C 6 )alkyl- phenyl, C ⁇ -C 3 oalkyl, Ci-Caoalkyl-CO- or a radical of formula -(CnH 2n -O-) m -R ⁇ o;
  • R 3 is hydrogen or -SO 2 -(C ⁇ -C 6 )alkylphenyl;
  • R and R 7 are d-C ⁇ alkylene or a radical of formula -(C n H 2n -O-) m -R ⁇ o
  • R 8 and R 9 are each independently of the other
  • R 10 is a direct bond or Ci-Ci ⁇ alkylene; n is a number from 2 to 6, and m is a number from 1 to 10, with the proviso that the total number of carbon atoms is at most 30; and Y is -OH or -SH.
  • the alkyl groups can be linear or branched and preferably contain 1 to 24 carbon atoms. Linear alkyl groups are preferred. Typical examples of alkyl are methyl, ethyl and the positional isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, and tricontyl.
  • -SO2-(Ci-C 6 )Alkylphenyl is preferably toluenesulfonyl.
  • C 2 -C3oAlkylene can be linear or branched and preferably contains 2 to 20, particularly preferably 2 to 16, carbon atoms.
  • Linear alkylene is preferred.
  • Typical examples are methylene, ethylene and the positional isomers of propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, and tricontylene.
  • n is preferably 2 to 4
  • m is preferably 2 to 6
  • R 10 is preferably either a direct bond or C 2 -C alkylene.
  • C ⁇ -C ⁇ alkylen ⁇ bridge groups which are interrupted by oxygen atoms are those which are derived from ethylene oxide, propylene oxide, butylene oxide or isobutylene oxide.
  • Ri and R 2 in the compounds of formula I are preferably each independently of the other hydrogen or linear C ⁇ 2 -C 24 alkyl, the carbon atom number of Ri and R 2 together preferably being from 10 to 20.
  • R 4 is preferably linear C 2 -C ⁇ 6 alkylene or a radical of formula -(C2H 4 -O-) m -R 10> wherein R 10 and m have the meanings cited above.
  • R 5 and R 6 in the compounds of formula II, Ila or lib are preferably each independently of the other linear C2-Ci2alkyl.
  • R 5 and R 6 are particularly preferably identical and are linear C2- C ⁇ alkyl.
  • R 7 in the compounds of formula Ila or lib is preferably linear C 2 -C 16 alkylene.
  • the compounds of formulae I, Ila and lib preferably have a pK a value of at least 8, particularly preferably of at least 10.
  • the pK a value can be adjusted by the choice and combination of Ri to R 7 .
  • the invention relates to a process for the preparation of the compounds of formulae I, Ila and lib, which comprises a) removing the phthalimide group in the compounds of formula Ic or He
  • the compounds of formula Ic can be prepared in a manner known per se by stepwise alkylation using different alkylating agents or by alkylation using an alkylating agent or acylating agent of the commercially available 3,6-diaminoacridine.
  • Suitable alkylating agents are, for example, dialkyl sulfates or monohalogen alkanes, preferably chloroalkanes, bromoalkanes and iodoalkanes.
  • Suitable acylating agents are, for example, carboxylic acid anhydrides and, preferably, carboxylic acid halides, typically carboxylic acid chlorides.
  • This reaction can be carried out in the presence of inert polar and aprotic solvents, typically ethers, alkylated acid amides and lactames or sulfones, and at elevated temperatures, e.g. from 50 to 150°C. It is expedient to add a hydrogen halide scavenger, typically alkali metal carbonates or tertiary amines and, preferably, sterically hindered tertiary amines.
  • the starting compound is 3,6-diaminoacridine which is reacted in a first step with p-toluenesulfonic acid chloride.
  • the purified reaction product is reacted first e.g. with a compound R 2 -Br at one nitrogen atom and e.g. with Br-FU-phthal imide at a second nitrogen atom. Further reaction with e.g. hydrazine hydrate gives a compound of formula I.
  • the compounds of formula lie are typically obtainable by reacting phthalic acid anhydride with 2 molar equivalents of 3-monoalkylaminophenol.
  • Another possible method of preparation consists in reacting 3-monoalkylaminophenol with 1 molar equivalent of 2- hydroxy-4-dialkylamino-2'-carboxylbenzophenone.
  • the reaction is conveniently carried out in an inert solvent, typically hydrocarbons or ethers.
  • Molar amounts of a condensing agent are usefully added, typically Lewis acids, concentrated sulfuric acid, perchloric acid or phosphoric acid.
  • the reaction temperature is typically in the range from 50 to 250°C.
  • the compounds of formula I, Ila and lib can be isolated in conventional manner by precipitation, crystallisation or extraction and, where required, can be purified by recrystallisation or by chromatographic methods. Said compounds are crystalline and dyed e.g. a red, reddish brown or reddish violet colour.
  • the p-toluenesulfonyl group can be removed by known methods, such as described in J. Chem. Soc. Chem. Com. 1973, 664.
  • a process for the preparation of the compounds of formula Ila or lib can typically be carried out such that 4-(2'-carboxy)benzoyl-3-hydroxy-N,N-diethylaniline is first placed in a reaction vessel and reacted with 3-methoxy-N-(3-aminopropyl)aniline.
  • the resulting reaction product is a compound of formula Ila or lib.
  • This compound can be further reacted by known methods, typically with methacryloyi chloride, again resulting in a compound of formula Ila or lib.
  • the compounds of formula I, Ila or lib are excellently suited for covalent attachment at polymers selected from the group consisting of polyurethanes, polyureas and polyurea- polyurethanes.
  • olefinically unsaturated monomers are acrylic acid, methacrylic acid, maleic acid, maleic acid anhydride, Ci-Caoacrylic acid ester and C ⁇ -C 3 omethacrylic acid ester, CrGaoacrylic acid amide and Ct-C ⁇ methacrylic acid amide, or acrylic acid amide and methacrylic acid amide, vinyl ester of C ⁇ -C2ocarboxylic acids, acrylonitrile, butadiene, isoprene, chlorobutadiene, styrene, ⁇ -methylstyrene, vinyl chloride, vinyl fluoride, vinylidene chloride and vinyl ether of C ⁇ -C3oalcohols.
  • the invention also relates to a copolymer which is plasticiser-free and which consists either
  • the copolymer is preferably formed by at least one diol or diamine and one diisocyanate.
  • the compounds of I, Ila or Mb are preferably present in an amount of 0.01 to 10 % by weight, more preferably of 0.1 to 5 % by weight and, most preferably, of 0.1 to 2 % by weight, based on the amount of polymer.
  • Copolymer A) can be polyurethane, polyurea or polyureapolyurethane.
  • Polymer A) is preferably a polyurethane consisting of polyethers of C 3 -C 6 alkanediols, polyoxyalkylenediols or hydroxy-terminated siloxanes and aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic-aliphatic or aromatic C 2 -C 2 odiisocyanates.
  • Preferred diisocyanates are those selected from the group consisting of 1 ,6-bisfjsocyanate]- hexane, 5-isocyanate-3-(isocyanatemethyl)-1 ,1 ,3-trimethylcyclohexane, 1 ,3-bis[5-iso- cyanate-1 ,3,3-trimethylphenyl]-2,4-dioxo-1 ,3-diazetidine, 3,6-bis[9-isocyanatenonyl]-4,5- di(1 -heptenyl)cyclohexene, bis[4-isocyanatecyclohexyl]methane, trans-1 ,4-bis[isocyanate]- cyclohexane, 1 ,3-bis[isocyanatemethyl]benzene, 1 ,3-bis[1-isocyanate-1 -methylethyl]- benzene, 1 ,4-bis[2-isocyanate-ethy
  • Particularly preferred diisocyanates are those selected from the group consisting of 1,6- bis[isocyanate]hexane, 5-isocyanate-3-(isocyanatemethyl)-1,1 ,3-trimethylcyclohexane, 2,4- bis ⁇ socyanate]toluene, 2,6-bispsocyanate]toluene, 2,4-/2,6-bis[isocyanate]toluene, bis[4- isocyanatecyclohexyl]methane or bis[4-isocyanatephenyl]methane.
  • Particularly suitable polyurethanes are obtained by reacting a) 5-45 % by weight of an aromatic, cycloaliphatic or linear aliphatic diisocyanate, b) 0-20 % by weight of a linear or branched C 2 -C ⁇ 2 alkylenediol c) 0-75 % by weight of a polytetrahydrofuran d) 0-10 % by weight of a polyethylene glycol e) 0-75 % by weight of a polypropylene glycol and f) 15-95 % by weight of a hydroxy-terminated or hydroxypropyl-terminated polydimethyl ⁇ siloxane g) 0.1-5 % by weight of a fluorophore of formula I, Ila or lib, where the percentages are based on the amount of polymer and the parts by weight of the components a) to g) give a sum of 100.
  • a thermoplastic, randomly segmented polyurethane is obtained.
  • the hydroxy-terminated or hydroxypropyl-terminated polydimethylsiloxane preferably has a molecular weight of 900 to 4500 dalton.
  • the polytetrahydrofuran preferably has a molecular weight of 1000 to 4500 dalton.
  • Polyethylene glycol preferably has a molecular weight of 600 to 2000 dalton
  • polypropylene glycol preferably has a molecular weight of 1000 to 4000 dalton.
  • the preparation of the polyurethanes can be carried out according to processes which are known per se.
  • the compounds of formula I, Ila or lib can either be added from the start to the reaction mixture for the preparation of polyurethane. However, it is also possible to react the compounds of formula I, Ila or Mb first with excess diisocyanate and then to mix the reaction product with the diol or polyol components. Another possibility consists in diluting the diol or polyol component with a hyperstoichiometric amount of diisocanate and and subsequently reacting the compounds of formula I with the excess diisocyanate.
  • the polymers obtained have essentially terminally bound fluorophors.
  • Another group of preferred copolymers is obtained by selecting the monomers from the compounds of the group consisting of acrylic acid, methacrylic acid, maleic acid, maleic acid anhydride, Ci-Caoacrylic acid ester and Ci-Csomethacrylic acid ester, C ⁇ -C 3 oacrylic acid amide and Ci-C ⁇ methacrylic acid amide or acrylic acid amide and methacrylic acid amide, vinyl ester of C ⁇ -C 2 ocarboxylic acids, acrylonitrile, butadiene, isoprene, styrene, ⁇ - methylstyrene, and vinyl ether of d-Csoalcohols and a compound of formula I, Ila or lib
  • the compounds of formula I, Ila or Mb are preferably present in an amount of 0.01 to 10 % by weight, preferably of 0.1 to 5 % by weight and, very particularly preferably, of 0.1 to 2 % by weight, based on the entire polymer.
  • the copolymers comprise a) 10 to 90 % by weight, preferably 20 to 80 % by weight and, particularly preferably, 30 to 70 % by weight, based on the polymer, of identical or different structural elements of formula III
  • R10 and Rn are each independently of the other H or C ⁇ -C 4 alkyl, X is -O- or -NRir, R ⁇ 2 is C C 2 oalkyl and R ⁇ 7 is H or Ci-C ⁇ oalkyI;
  • R ⁇ 3 and R ⁇ 4 are each independently of the other H, F, Cl or CrC alkyl
  • R 15 and R ⁇ 6 are each independently of the other H, F, Cl, C ⁇ -C alkyl, -COOH, -COO-CrC 5 alkyl, -CONHC ⁇ -C 5 alkyl or -CON(R ⁇ 7 )C ⁇ -C 5 alkyl
  • R15 is H and R ⁇ 6 is -CN, phenyl, chlorophenyl, C ⁇ -C ⁇ alkoxy or C 2 - C ⁇ 8 acyloxy.
  • R10 is preferably H or methyl and Rn is preferably H.
  • X is preferably -O-.
  • R 12 is preferably C -C ⁇ ⁇ alkyl.
  • Illustrative examples of R ⁇ 2 are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, dodecyl, tetradecyl and hexadecyl.
  • R 3 is preferably H or methyl
  • R 14 is preferably H
  • R15 is preferably H
  • R 16 is preferably -CN, phenyl, -COO-C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy or C 2 -C 6 acyloxy.
  • acyloxy are acetyloxy, propionyloxy, butyroyloxy, pentanoyloxy and hexanoyloxy.
  • a particularly preferred copolymer is that wherein the monomers forming the polymer are selected from the group consisting of C ⁇ -C ⁇ 6 acrylic acid alkyl esters, C ⁇ -C ⁇ 6 methacrylic acid alkyl esters, acrylamide, methacrylamide and the corresponding N-substituted derivatives, or acrylonitrile.
  • the resulting fluorophores are essentially terminally or randomly distributed in the polymers.
  • alkylenetriols in minor amounts, typically 1 ,1 ,1-tris(hydroxymethyl)- ethane in an amount of 0.1 to 5 % by weight, based on the polymer. Under these conditions, no detectable crosslinking takes place yet and the resultant polyurethane remains soluble in organic solvents.
  • copolymer is formed from olefinically unsaturated monomers
  • diolefinic monomers can also be added in minor amounts as crosslinkers.
  • the polymer preferably has a glass transition temperature in the range from -150°C to 50°C, particularly preferably from -125°C to -40°C.
  • the molecular weight of the polymer is preferably from 10000 to 250 000 dalton, more preferably from 10 000 to 100000 dalton and, most preferably, from 10 000 to 30 000 dalton.
  • the dielectric constant of the polymer at 100 Hz and at room temperature is preferably from 2 to 25, particularly preferably from 5 to 15.
  • the optical transparence is preferably in the range from 400 to 1200 nm, particularly preferably from 400 to 900 nm.
  • the invention also relates to an optical sensor consisting of
  • the carrier can, for example, be constructed from a plastic material, typically polycarbonate or acrylic glass, mineral materials or glass and may be in any form, e.g. plates, cylinders, tubes, ribbons or filaments. Glasses are preferred.
  • the layer thickness on the carrier can be, for example, from 0.01 to 100 ⁇ m, preferably from 0.1 to 50 ⁇ m, more preferably from 0.1 to 30 ⁇ m and, particularly preferably, from 0.1 to 10 ⁇ m.
  • Preferred salts containing lipophilic anions are alkali metal salts and ammonium salts with unsubstituted or substituted tetraphenylborates.
  • Particularly preferred cations are Li + , Na + , K ⁇ NH 4 + , and the ammonium cations of primary, secondary and tertiary amines as well as quaternary ammonium cations containing 1 to 60 carbon atoms.
  • ammonium cations are methyl ammonium, ethyl ammonium, propyl ammonium, butyl ammonium, hexyl ammonium, octyl ammonium, decyl ammonium, dodecyl ammonium, tetradecyl ammonium, hexadecyl ammonium, octadecyl ammonium, dimethyl ammonium, diethyl ammonium, dibutyl ammonium, butylmethyl ammonium, dioctyl ammonium, didoceyl ammonium, dodecylmethyl ammonium, trimethyl ammonium, triethyl ammonium, tripropyl ammonium, tributyl ammonium, trioctyl ammonium, tridodecyl ammo ⁇ nium, dodecyldimethyl ammonium, didodecylmethyl ammonium, te
  • Borate anion is preferably unsubstituted tetraphenylborate or tetraphenylborate which is substituted at the phenyl groups by one or more than one C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, halogen, typically F, Cl, Br or I, or trifluoromethyl.
  • the salts containing lipophilic anions serve as negative charge exchange for cations to be determined which have diffused into the active layer and which are complexed there.
  • the salts containing lipophilic anions can also be salts of polymers containing acid or basic groups, typically polysulfonic acids or polycarboxylic acids.
  • the amount of salts containing lipophilic anions is preferably from 0.01 to 10 % by weight, particularly preferably from 0.1 to 5 % by weight, based on the amount of polymer.
  • lonophores are organic, natural or synthetic compounds which contain several, mostly alternating, electron-rich hetero atoms, typically S, N and, preferably, O, in an open-chain or cyclic carbon chain and which are capable of selectively complexing the ions to be determined.
  • the natural compounds are often macrocyclic compounds such as valinomycin which is capable of selectively binding potassium cations. Another example is nonactin.
  • a large group of ionophores consists of the macrocyclic polyethers (crown ethers) which, depending on geometry and size, are capable of complexing different metal cations.
  • Other examples of ionophores to be mentioned are coronandenes, cryptandenes and calixarenes.
  • a typical example of open-chain ionophores are the podandenes. Such ionophores are described, inter alia, in US-A-4645744.
  • the nonionic ionophore preferably contains an open-chain carbon chain with several oxygen atoms.
  • Particuarly preferred are (R,R)-N,N'-bis[11-ethoxycarbonylundecyl]-N,N',4,5- tetramethyl-3,6-dioxaoctanediamide, N,N-dicyclohexyl-N',N'-dioctadecyl-3-oxapentane- diamide or N,N,N',N'-tetracyclohexyl-3-oxapentane diamide.
  • the polymer contains the ionophore preferably in an amount of 0.01 to 10 % by weight, particularly preferably in an amount of 0.1 to 5 % by weight, based on the amount of polymer.
  • the optical sensor preferably contains valinomycin as potassium ionophore.
  • the preparation of such membranes can be carried out in a manner known per se, typically by dissolving the composition in an organic solvent and then casting it to a film with subsequent removal of the solvent. Once the solvent is removed, the film can be stripped from the base, resulting in a self-supporting membrane. Further possible processes for the preparation of the membrane are those known from coating technology, typically spinning, spraying or doctor coating processes. Spin-coating processes are preferred.
  • Suitable solvents are ethers, esters, acid amides and ketones.
  • Readily volatile solvents are particularly suitable, preferably tetrahydrofuran.
  • thermoplastic processing In addition to these processes, which comprise first dissolving the composition, moulding it and and then removing the solvent by evaporation, heat moulding processes are also possible because the composition is a thermoplastic material. Suitable heat moulding processes are extrusion, injection moulding, compression moulding or blow moulding processes such as those known from thermoplastic processing.
  • the membrane can be transparent or slighlty opaque.
  • the membrane is preferably transparent.
  • the fluorophores to be used according to this invention have very suitable ranges of absorption and emission wavelengths which permit the use of known and inexpensive light sources, for example halogen or xenone lamps or light-emitting diodes. Detectors suitable for use are e.g. photodiodes. In addition, the fluorophores have high extinction coefficients and can afford high quantum yields.
  • the high lipophilic properties, high basicity and the great dynamic range of the change between the fluorescence of the protonated and deprotonated form meet in particular the high demands made on an optical determination of ions based on the measurement of the fluorescence. Cations as well as anions can be determined.
  • Suitable cations are, for example, cations of the metals of the first to fifth main group of the periodic system of the elements, the lanthanides and actinides.
  • Typical examples of metals are Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, B, Al, Ga, In, Tl, Sn, Pb, Sb, Bi, Cu, Ag, Au, Zn, Cd, Hg, Sc, Y, Ti, Zr, Hf, Cr, Mo, W, Mn, Fe, Co, Ni, Ru, Os, Rh, Ir, Pt, Pd, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Yb, Lu, Ac, Th, Pa, U, Np, Pu.
  • Preferred cations are the alkali metal cations and alkaline earth metal cations, in particular Li ⁇ Na + , K ⁇ Mg + , Ca 2+ and Sr 2* , and, more preferably, K + , Na + and Ca *+ .
  • Suitable ammonium cations are e.g. NH 4 + as well as the cations of protonated primary, secondary and tertiary amines and also quaternary ammonium.
  • the amines can contain 1 to 40, preferably 1 to 20 and, more preferably, 1 to 12, carbon atoms.
  • the quaternary ammonium can contain 4 to 40, preferably 4 to 20 and, more preferably, 4 to 16, carbon atoms.
  • the anions to be determined can be derived from mineralic acids, oxygen acids and inorga ⁇ nic complex acids.
  • Illustrative examples are the halides and pseudohalides F, Cl ' , Br “ , I “ , N 3 " , CN “ , OCN “ and SCN “ ; anions of the inorganic oxygen acids NO 2 " , NO 3 " , COs 2" , P ⁇ SO 4 2" , CIO 4 " , MnO 4 " and CIO 3 ' ; anions of the inorganic complex acids Fe(CN) 6 4" and CofCNJe 3" ; the anions of carboxyiic acids, phenols; nucleotide anions such as adenosine phosphate.
  • the optical sensor is particularly suitable for the quantitative determination of ions, in particular of cations, very particularly of metal cations, typically potassium cations, in aqueous environment, preferably using fluorescence spectrometry.
  • the determinations can be carried out in short time at high accuracy even at low concentrations (e.g. in the ⁇ -molar range up to the nanomolar range) because the pH-dependent equilibria of the complexing reactions and of the proton exchange adjust quickly and because the fluorophores are distinguished by high fluorescence quantum yields and sensitivity.
  • the analyses can be typically carried out direct in body fluids (blood, urine, serum), natural waters or waste waters, while possibly interfering cations can be specifically bound or removed beforehand.
  • the novel composition is particularly suitable for the determination of physiological amounts of cations in aqueous media which, in the case of potassium, may be e.g. in the range from about 0.5 to 10 mmol.
  • fluorescence spectroscopy In addition to the preferred fluorescence spectroscopy, other optical methods of measurement can also be used, typically surface plasmon resonance spectroscopy, ab ⁇ sorption spectroscopy, reflection spectroscopy, interferometry or surface-enhanced Raman or fluorescence spectroscopy.
  • the invention also relates to a process for the optical determination of ions in aqueous test samples by contacting a sensor of this invention with said aqueous test sample and then measuring the change in fluorescence of the fluorophore in the polymer layer.
  • the process of this invention can typically be carried out such that the carrier is mounted with the active polymer layer in an optical cell wherein the active layer is contacted with the test sample.
  • the optical cell contains a window through which the active layer can be irradiated to excitation and the emitted fluorescent radiation can be measured with a spectrofluorometer. The wavelengths are adjusted such that maximum absorption is obtained for the irradiation and maximum emission is obtained for the fluorescence measurement. The intensity is measured as a function of time.
  • the measuring system can be such that measurement is carried out discontinuously or continuously e.g. by pumping the measuring solution through the measuring cell.
  • the system can first be calibrated using test samples of known concentration by applying the concentrations as function of the intensity of the fluorescence.
  • pH buffers are expediently added to the test sample because, owing to the pH dependence of the absorption spectrum of the fluorophore and consequently also of the fluorescence intensity of the fluorophore, the sensitivity of the measurement depends on the pH of the measuring solution. However, in another embodiment of this invention said pH dependence can also be determined and be taken into account in the calculations.
  • the pH range of the test sample can be, for example, 4 to 8, preferably 6.5 to 7.5.
  • Suitable buffers are typically citrate buffers and phosphate buffers. Further buffer systems are described in US-A-4 645 744, in particular also such buffers which are incorporated direct into the active layer to avoid the addition to the test sample.
  • the invention also relates to the use of the optical sensor for the fluorescence spectroscopic analysis of cations or anions.
  • Ts in the structural formulae hereinbelow denotes a tosyl radical.
  • Example A7 The compound 107 of Example A7 is stirred into a mixture of 5 parts of acetic acid and 2 parts of sulfuric acid (25 ml in all) for 18 hours at room temperature. The mixture is then poured in water and extracted with methylene chloride. The organic phase is washed with bicarbonate solution, dried and concentrated by evaporation. Yield: 1.61g pure product.
  • Example B6 In in general accordance with the process described in Helv. Chim. Acta 1988, 71, 2087, the compound 206 of Example B6 is activated at the free carboxylic acid functional group and then reacted with diethanolamine over 72 hours at room temperature. Yield: 73%. MS(FD): 671.
  • Example B8 Preparation of compound 208
  • the polymer is precipitated by being poured in 500ml of methanol and is then isolated by filtration and dried under vacuum at 20°C. The product obtained is dissolved once more in
  • Example C2 In a three-necked flask equippped with stirrer, 1.0 g of polytetrahydrofuran (M n
  • the resulting pink fluorescent solution is combined with the polymer solution mentioned above and the reaction is allowed to proceed for a further 3 hours at 60°C.
  • the polymer is then precipitated by being poured in 500ml of methanol and is then isolated by filtration and dried under vacuum at 20°C.
  • the product is dissolved once more in 20 ml of tetrahydrofuran and precipitated in 500 ml of methanol, giving a pink polymer.
  • Example C3 4.00 g of Tecoflex® polyurethane, supplied by Thermedics, together with 0.05mmol/g of OH terminal groups and 0.002 g of diazabicyclooctane are dissolved in a mixture of 30 ml of tetrahydrofuran and 25 ml of dimethylformamide and then a solution is added consisting of of 0.055 g of methylene diphenyl diisocyanate and 0.067 g of the compound of formula 207 of Example B7 in 5 ml of DMF. The mixture is allowed to react for 16 hours at 60°C. Further processing is carried out in general accordance with the procedure of Examples 1 and 2. The yield is 3.05 g (74 % of theory) of pink polymer.
  • Example C4 In a vial, equipped with a three-way tap connected to vacuum and nitrogen, 50 mg of the compound 209 of Example B9 are dissolved in 0.16 g (2.9 mmol) of acrylonitrile. To this solution are added 4.84 g (26.3 mmol) of 2-ethylhexylacrylate and 5 mg of azoisobutyronitrile (AIBN). The vial is closed and the atmosphere is exchanged three times by a freezing/thawing cycle with nitrogen. The vial is kept in a water bath at 60°C for 2 days. The viscous contents of the vial are then dissolved in 50 ml of toluene at 50°C and the polymer is precipitated in 1000ml of methanol.
  • AIBN azoisobutyronitrile
  • the pale red polymer is filtered, dried, dissolved again and then precipitated again under the same conditions. Drying is carried out over 24 hours under high vacuum. The yield is 1.9 g (38%) and the glass transition temperature is -58°C. The inherent viscosity of a 0.5 % solution in THF at 25°C is
  • Example D1 Pretreated glass is used as carrier material. Round glass panes (diameter 18 mm, thickness 0.17 mm) are immersed for 1 hour into a solution of 10 vol % of dimethyl- dodecylchlorosilane in isopropanol. The glass panes are then washed in succession with 200 ml each of isopropanol, ethanol and methanol and dried for 1 h at 1 10°C. The adhesion of the membrane layer on the hydrophobised surface is improved.
  • the sensor membrane is prepared by dissolving 40 mg of the polymer described in Example C1 , 1.5 mg of valinomycin and 1.2 mg of potassium tetrakis 3,5- bis(trifluoro- methylphenyl)borate in 1.2 ml of tetrahydrofuran.
  • the glass carriers are mounted in the chamber of a spin-coating apparatus (Optocoat OS 35var, Wilier Company, CH-8484 Weisslingen).
  • the chamber is rinsed with 10 ml of tetrahydrofuran and rotated for 2 min at 8000 rpm.
  • 50 ⁇ l of the respective coating solution are pipetted on to the glass carrier which is then rotated for a further 10 sec.
  • the membrane-coated glass carrier is taken out and dried for 10 min in the air.
  • the coated glass carriers are mounted in an optical cell wherein the membrane is in contact with the measuring liquid.
  • the membrane In the optical cell the membrane can be optically excited and the fluorescence radiation can be measured.
  • the optical cell is placed in a spectrofluorometer (Pekin-Elmer LS-50). The absorption and emission wavelengths are adjusted to the respective maxima of the fluorophores used in the membrane.
  • the membrane is contacted with an aqueous solution of Kcl or CaCI 2 of defined concentration by pumping the solution at a rate of 1 ml/min through the cell and determining the change in fluorescence intensity. Rinsing with potassium ion-free buffer solutions is carried out before and after each measurement and the fluorescence intensity is measured in order to determine the base line.
  • the fluorescence intensity (measured as change in voltage in the photodiode) at the respective potassium concentration for the fluorophore is listed below.
  • Example D2 The procedure of Example D1 is repeated, the membrane for the sensor being composed of 20 mg of the polymer of Example C2, 1.5 mg of valinomycin and 1.2 mg of potassium tetrakis 3,5- bis(trifluoromethylphenyl)borate. The following values are obtained:
  • Example D3 The procedure of Example D1 is repeated, the membrane for the sensor being composed of 40 mg of the polymer of Example C2, 3.0 mg of valinomycin and 2.0 mg of potassium tetrakis 3,5- bis(trifluoromethylphenyl)borate. The following values are obtained:
  • Example D4 The procedure of Example D1 is repeated, the membrane for the sensor being composed of 75 mg of the polymer of Example C4, 1.5 mg of valinomycin and 1.2 mg of potassium tetrakis 3,5-bis(trifluoromethylphenyl)borate. The following values are obtained:

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Abstract

L'invention concerne des composés de formules (I), (IIa) ou (IIb) dans lesquelles R1, R2, R5 et R6 représentent chacun indépendamment hydrogène, -SO2-alkyle(C1-C6)-phényle, alkyle C1-C30, alkyle C1-C30-CO- ou un radical de formule -(CnH2n-O-)m-R10; R3 représente hydrogène ou -SO2-alkylphényle(C1-C6); R4 et R7 représentent alkylène C1-C30 ou un radical de formule -(CnH2n-O-)m-R10; Z représente un groupe fonctionnel choisi dans le groupe constitué par -OH, -SH, -NH2, -COOH, -NCO, -CO-NR8YR9Y, -NH-CO-CH=CH2, -NH-CO-C(CH3)=CH2; R8 et R9 représentent chacun indépendamment alkylène C1-C30; R10 représente une liaison directe ou alkylène C1-C12; n est un nombre compris entre 2 et 6 et m est un nombre compris entre 1 et 10, à condition que le nombre total des atomes de carbone ne dépasse pas 30; et Y représente -OH ou -SH. Ces composés sont utilisés en tant que comonomères dans la préparation de membranes copolymères destinées à des capteurs d'ions dépourvus de plastifiant.
PCT/EP1996/003954 1995-09-21 1996-09-10 Fluorophores a liaison polymere utilises en tant que capteurs optiques d'ions WO1997011067A1 (fr)

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AU69888/96A AU6988896A (en) 1995-09-21 1996-09-10 Polymer-bound fluorophores as optical ion sensors
JP9512206A JP2000501069A (ja) 1995-09-21 1996-09-10 光イオンセンサーとしてのポリマー結合フルオロフォア
EP96931059A EP0876363A1 (fr) 1995-09-21 1996-09-10 Fluorophores a liaison polymere utilises en tant que capteurs optiques d'ions

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WO1999007793A1 (fr) * 1997-08-04 1999-02-18 Nycomed Amersham Plc Produit intermediaire colorant et procede
WO2000016074A1 (fr) * 1998-09-15 2000-03-23 Joanneum Research Forschungsgesellschaft Mbh Detecteur optochimique et son procede de production
WO2000054039A1 (fr) * 1999-03-10 2000-09-14 Elizabeth Anne Howlett Hall Matiere polymere selective
WO2001059156A2 (fr) * 2000-02-10 2001-08-16 Yissum Research Development Company Of The Hebrew University Of Jerusalem Detection de liaison d'especes chargees, au moyen de sondes sensibles au potentiel ou au ph
US6984718B2 (en) 1998-07-21 2006-01-10 Cytovia, Inc. Fluorescence dyes and their applications for whole-cell fluorescence screening assays for caspases, peptidases, proteases and other enzymes and the use thereof
US20070167594A1 (en) * 2003-10-17 2007-07-19 Reverse Proteomics Research Institute Co., Ltd Affinity resin
CN102153700A (zh) * 2011-03-16 2011-08-17 江南大学 一种基于荧光比色变化检测汞离子的亲水性聚合物的制备及其应用
DE102011118618A1 (de) * 2011-11-16 2013-05-16 Forschungszentrum Jülich GmbH Optode
US8865249B2 (en) 2002-05-22 2014-10-21 Dexcom, Inc. Techniques to improve polyurethane membranes for implantable glucose sensors
US8909314B2 (en) 2003-07-25 2014-12-09 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US8954128B2 (en) 2008-03-28 2015-02-10 Dexcom, Inc. Polymer membranes for continuous analyte sensors
US9173607B2 (en) 2008-03-28 2015-11-03 Dexcom, Inc. Polymer membranes for continuous analyte sensors
US9328371B2 (en) 2001-07-27 2016-05-03 Dexcom, Inc. Sensor head for use with implantable devices
US9339223B2 (en) 1997-03-04 2016-05-17 Dexcom, Inc. Device and method for determining analyte levels
US9339222B2 (en) 2008-09-19 2016-05-17 Dexcom, Inc. Particle-containing membrane and particulate electrode for analyte sensors
US9439589B2 (en) 1997-03-04 2016-09-13 Dexcom, Inc. Device and method for determining analyte levels
US9549693B2 (en) 2002-05-22 2017-01-24 Dexcom, Inc. Silicone based membranes for use in implantable glucose sensors
US9763609B2 (en) 2003-07-25 2017-09-19 Dexcom, Inc. Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise
US10300507B2 (en) 2005-05-05 2019-05-28 Dexcom, Inc. Cellulosic-based resistance domain for an analyte sensor
US10376143B2 (en) 2003-07-25 2019-08-13 Dexcom, Inc. Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise
US10791928B2 (en) 2007-05-18 2020-10-06 Dexcom, Inc. Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise
US11730407B2 (en) 2008-03-28 2023-08-22 Dexcom, Inc. Polymer membranes for continuous analyte sensors

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EP0561738A1 (fr) * 1992-03-17 1993-09-22 Ciba-Geigy Ag Composés de fluorane utile comme composés chromogènes
EP0623599A1 (fr) * 1993-03-26 1994-11-09 Ciba-Geigy Ag Détecteurs optiques pour la détermination de cations

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EP0561738A1 (fr) * 1992-03-17 1993-09-22 Ciba-Geigy Ag Composés de fluorane utile comme composés chromogènes
EP0623599A1 (fr) * 1993-03-26 1994-11-09 Ciba-Geigy Ag Détecteurs optiques pour la détermination de cations

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US9339223B2 (en) 1997-03-04 2016-05-17 Dexcom, Inc. Device and method for determining analyte levels
WO1999007793A1 (fr) * 1997-08-04 1999-02-18 Nycomed Amersham Plc Produit intermediaire colorant et procede
US6984718B2 (en) 1998-07-21 2006-01-10 Cytovia, Inc. Fluorescence dyes and their applications for whole-cell fluorescence screening assays for caspases, peptidases, proteases and other enzymes and the use thereof
WO2000016074A1 (fr) * 1998-09-15 2000-03-23 Joanneum Research Forschungsgesellschaft Mbh Detecteur optochimique et son procede de production
US6432363B2 (en) 1998-09-15 2002-08-13 Joanneum Research Forschungagesellschaft Mbh Optochemical sensor
WO2000054039A1 (fr) * 1999-03-10 2000-09-14 Elizabeth Anne Howlett Hall Matiere polymere selective
AU2001232211B2 (en) * 2000-02-10 2005-08-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Detection of binding of charged species using pH- or potential-sensitive probes
WO2001059156A2 (fr) * 2000-02-10 2001-08-16 Yissum Research Development Company Of The Hebrew University Of Jerusalem Detection de liaison d'especes chargees, au moyen de sondes sensibles au potentiel ou au ph
US7056653B2 (en) 2000-02-10 2006-06-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Detection of binding of charged species using PH- or potential-sensitive probes
WO2001059156A3 (fr) * 2000-02-10 2002-03-28 Yissum Res Dev Co Detection de liaison d'especes chargees, au moyen de sondes sensibles au potentiel ou au ph
US9328371B2 (en) 2001-07-27 2016-05-03 Dexcom, Inc. Sensor head for use with implantable devices
US9804114B2 (en) 2001-07-27 2017-10-31 Dexcom, Inc. Sensor head for use with implantable devices
US8865249B2 (en) 2002-05-22 2014-10-21 Dexcom, Inc. Techniques to improve polyurethane membranes for implantable glucose sensors
US10154807B2 (en) 2002-05-22 2018-12-18 Dexcom, Inc. Techniques to improve polyurethane membranes for implantable glucose sensors
US10052051B2 (en) 2002-05-22 2018-08-21 Dexcom, Inc. Silicone based membranes for use in implantable glucose sensors
US9179869B2 (en) 2002-05-22 2015-11-10 Dexcom, Inc. Techniques to improve polyurethane membranes for implantable glucose sensors
US11020026B2 (en) 2002-05-22 2021-06-01 Dexcom, Inc. Silicone based membranes for use in implantable glucose sensors
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US9801574B2 (en) 2002-05-22 2017-10-31 Dexcom, Inc. Techniques to improve polyurethane membranes for implantable glucose sensors
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US8909314B2 (en) 2003-07-25 2014-12-09 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US9597027B2 (en) 2003-07-25 2017-03-21 Dexcom, Inc. Oxygen enhancing membrane systems for implantable devices
US10376143B2 (en) 2003-07-25 2019-08-13 Dexcom, Inc. Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise
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US20070167594A1 (en) * 2003-10-17 2007-07-19 Reverse Proteomics Research Institute Co., Ltd Affinity resin
US10300507B2 (en) 2005-05-05 2019-05-28 Dexcom, Inc. Cellulosic-based resistance domain for an analyte sensor
US10791928B2 (en) 2007-05-18 2020-10-06 Dexcom, Inc. Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise
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DE102011118618A1 (de) * 2011-11-16 2013-05-16 Forschungszentrum Jülich GmbH Optode

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